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Keywords:

  • haematopoietic stem cell transplants;
  • gene polymorphisms

Summary

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

Analysis of non-histocompatibility leucocyte antigen (HLA) functional genomics, together with conventional risk factors in haematopoietic stem cell transplantation (HSCT) can lead to predicting outcome in HLA-matched sibling transplant recipients. Polymorphisms of cytokine genes including tumour necrosis factor α, interleukin-10, interferon γ and interleukin (IL)-6, associate with more severe acute graft-versus-host disease (aGvHD). Donor genotype for IL-1 receptor antagonist (IL-1Ra) has been associated with reduced aGvHD severity. Other genotypes (patient IL-1Ra, IL-6 and donor IL-1α) have been associated with chronic GvHD, or overall survival (Vitamin D receptor and oestrogen receptor). Polymorphisms within genes associated with host defence/inflammatory responses (mannose binding lectin genes, myeloperoxidase genes and the FCγ receptors) have been associated with infections. Polymorphisms of pharmacogenes, such as methylenetetrahydrofolate-reductase, have been associated with aGvHD and other post-transplant complications. The NOD2 gene polymorphism, associated with Crohn's disease, has been shown to be associated with risk of gut GvHD. The majority of the studies have been carried out in single centre HLA-matched sibling cohorts and in relatively few matched unrelated donor transplants. This review gives an overall perspective of the current field of non-HLA genetics with regard to HSCT outcome, clinical relevance and potential application of the results to clinical management of HSCT.

Haematopoietic stem cell transplantation (HSCT) is one area of stem cell research where major advances in the cure of haematological disorders, such as leukaemia and lymphoma, inherited immune disorders and aplastic anaemia, have been made. Despite this success (because of the advances in understanding of the immune system and the therapeutic role and function of bone marrow stem cells in treatment) the overall survival rate after HSCT is only 40–60%. The cure of such patients is hampered by clinical complications that arise post-transplant. These are largely the result of a lack of understanding of acceptance and rejection mechanisms and genetic differences that exist between a given patient and donor. These differences include transplantation antigens [major histocompatibility antigen and minor histocompatibility antigens (mHag)] and, more recently, non-histocompatibility leucocyte antigen (HLA) functional gene polymorphisms, which can result in a greater risk and severity of transplant-related complications.

In addition, many donor-, recipient-, disease- and transplant-related factors (such as age, gender, cytomegalovirus serologic status, disease type, conditioning regimen or haematopoietic stem cell source and dose), can affect occurrence and severity of HSCT complications. Although HLA compatibility remains the central means of selecting donors, the sequencing of the human genome has revealed numerous non-HLA encoded single nucleotide polymorphisms (SNPs) whose significance in allogeneic HSCT has only just started to be investigated. The polymorphisms within the regulatory sequences of genes may alter, for example, the amount of cytokine produced, the degree of receptor expression, metabolism of drugs or response to infection. This review summarizes the current field of non-HLA genetics with regard to patient and/or donor genotype which may be associated with HSCT outcome. This includes studies where genotypes appear to influence occurrence and severity of graft-versus-host disease (GvHD), time to neutrophil and platelet recovery, toxicities related to the drugs used in preparative regimens and GvHD prophylaxis, infectious episodes and survival after HSCT. Figure 1 summarizes an overview of where non-HLA genetics involving, for example, SNPs and microsatellites of cytokine genes and other genes appear to play a role in influencing recovery and survival post-HSCT.

image

Figure 1. Transplant conditioning regimens can lead to the release of cytokines pretransplant in the patient, which may be dependent on genetic polymorphisms. Certain patients therefore may be predisposed to releasing high levels of certain cytokines pre- and post-transplant during the ‘cytokine storm’ and therefore be more predisposed and/or protected (depending on the cytokine release e.g. TNFαversus IL-10) from acute or chronic GvHD. Incoming donor marrow T cells will also be genetically predisposed to release high or low levels of certain cytokines (donor cytokine response). This will be influenced by the degree of GvHD prophylaxis and or T-cell depletion strategies. Response to drug conditioning and prophylaxis regimes will also be influenced by the patient individual genotype for response to and metabolism of these types of drugs. During immune reconstitution and engraftment, when the patient is at risk of bacterial and viral infection, several gene polymorphisms of the genes associated with the patient response, such as myeloperoxidase (MPO), mannose binding lectin (MBL), Fcγ receptor and NOD2/CARD15 genes may influence the success or failure of a patient to eradicate infection. Certain gene polymorphisms associated with Vitamin D receptor and estrogen receptor have been associated with survival, possibly by influencing successful immune reconstitution.

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Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

Acute GvHD incidence following allogeneic HSCT from HLA-identical donor siblings is 30–80% and can be fatal in up to 50% of cases. The release of pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, IL-8 and tumour necrosis factor α (TNFα) during radiation and chemotherapy conditioning regimens is involved in the activation of antigen-presenting cells, apoptotic damage of GvHD target tissues, induction of donor T-cell activation, and upregulation of recipient HLA and adhesion molecule expression. Accelerated tissue damage then ensues from activated T cells and natural killer (NK) cells with release of predominantly T-helper 1 (Th1) type cytokines [IL-2, interferon gamma (IFNγ), TNFα] resulting in a ‘cytokine storm’. Although T cells are central to the initiation of GvHD, proinflammatory mediators, such as IL-1 and TNFα, are alone capable of inducing the pathological changes of GvHD (Reddy & Ferrara, 2003). Growing evidence suggests that the cascade of inflammatory cytokines is also involved in complications other than GvHD, such as interstitial pneumonitis (IP) and veno-occlusive disease (Holler et al, 2000). The impact of gene polymorphisms on the susceptibility to infection has recently been investigated (Mullighan et al, 2002; Rocha et al, 2002). Lipopolysaccharide (LPS) and other bacterial compounds are important co-stimulators of antigen presenting cells, thus modulating the alloreaction, and the LPS response is strongly influenced by cytokine gene polymorphisms (CGPs). Only recently, contribution of polymorphisms involving the Toll-like receptors (TLRs) and the intracytoplasmatic sensors (NOD2/CARD15 proteins) of bacterial compounds have been related to complications of allogeneic HSCT (Lorenz et al, 2001; Holler et al, 2004). Taken together it is now evident that the genetic make-up of the recipient and the donor can strongly influence the success or failure of HSCT (see Table I).

Table I.  Cytokine gene polymorphisms and their associations with graft-versus-host disease (GvHD) after allogeneic HSCT.
Cytokine gene polymorphismProposed function of polymorphismEffect of patient genotype on HSCT outcomeEffect of donor genotype on HSCT outcome
  1. TNF, tumour necrosis factor; IL, interleukin; IL-1 Ra, interleukin one receptor antagonist; IFN, interferon; TGF, transforming growth factor.

 Pro-inflammatory cytokines
IL-6−174G allele associated with increased IL-6 productionIncreases acute and chronic GvHD in HLA-matched sibling cohorts (Cavet et al, 1999; Sociéet al, 2001) 
IFNγ Intron 1 alleleLower in vitro IFNγ productionIncreased acute GvHD in HLA-matched sibling cohorts (Cavet et al, 2001) 
IL-1 gene family  Associates with chronic GvHD in HLA-matched siblings (Cullup et al, 2003)
IL-1α 889; intron 6 VNTR Improved survival decreases TRM in MUD transplants (MacMillan et al, 2003a)Improved survival decreases TRM in MUD transplants (MacMillan et al, 2003a)
IL-2 (−330 G/T) Increase in acute and chronic GvHD (MacMillan et al, 2003b) 
TNFd3Upregulates TNFα productionIncreases aGvHD in HLA-matched sibling HSCT (Middleton et al, 1998; Cavet et al, 1999) No association with unrelated cord blood transplantation (Kögler et al, 2002) 
TNFαTNFβ (Ncol) Severe toxic complications (Bogunia-Kubik et al, 2003) 
TNF receptorUnknownIncidence of acute GvHD HLA-matched siblings HSCT (Stark et al, 2003)More severe GvHD in HLA matched unrelated donor HSCT (Ishikawa et al, 2002)
TNFRII 196R(TNFRII receptor stimulates T-cell proliferation and alloimmune responses) Incidence of chronic GvHD HLA-matched siblings HSCT (Stark et al, 2003)
 Anti-inflammatory cytokines
IL-10−1064(12–15)Haplotype associated with decreased production of IL-10Increase in acute GvHD in BMT (Middleton et al, 1998; Cavet et al, 1999) Acute GvHD (Lin et al, 2003) No association in unrelated cord blood transplantation (Kögler et al, 2002)Chronic GvHD (Sociéet al, 2001; Rocha et al, 2002) Acute GvHD (Lin et al, 2003) No association in unrelated cord blood transplantation (Kögler et al, 2002)
IL-1 Ra VNTR VNTR intron 2 Downregulates pro-inflammatory effects of IL-1Increases chronic GvHD and increased IL-1 Ra production in HLA-matched siblings (Cullup et al, 2003; Rocha et al, 2002)Less severe acute GvHD in HLA-matched siblings (Cullup et al, 2001; Rocha et al, 2002)
TGFβTGFβ-509 TGF-β1 codon 10 leucine/praline No association with TGFβ−509 with incidence of GvHD or outcome in HLA-matched sibling cohort (Cavet et al, 2001)No association with TGFβ−509 with incidence of GvHD or outcome in HLA-matched sibling cohort (Cavet et al, 2001)
TGFβ-codon 25 (G/G) TGFβ-codon 10Increased production of TGFβDevelopment of GvHD (Hattori et al, 2002)Association with GvHD incidence and high TGFβ producers in HLA-matched sibling and matched unrelated cohorts (Leffell et al, 2001)
TGF-β1 receptor II (1167C/T) TGF-β I receptor II and development of GvHD (Hattori et al, 2002) 

Cytokine gene polymorphisms

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

Cytokine gene polymorphisms occurring within the 5′ or 3′ regulatory sequences of genes may alter the structure of the transcription factor binding sites within gene promoters and therefore alter the amount of cytokine produced, for example, upon allogeneic stimulation or infection. Many of the reported CGPs occur within apparent regulatory regions of the gene. Within normal populations, high or low producers of cytokines naturally exist because of the inherited gene polymorphisms. Initial studies within the solid organ transplant setting demonstrated that patients with high producer TNF and low producer IL-10 genotypes were more likely to reject their solid organ graft (Turner et al, 1995, 1997a,b). These studies have recently been extended to the HLA-matched sibling and unrelated HSCT settings, and a number of other CGPs have now been associated with GvHD and HSCT transplant outcomes (Brok et al, 1998; Fishman et al, 1998; Middleton et al, 1998; Cavet et al, 1999, 2001; Grainger et al, 1999; Cullup et al, 2001, 2003; Sociéet al, 2001; Hattori et al, 2002; Ishikawa et al, 2002; Kögler et al, 2002; Rocha et al, 2002; Lin et al, 2003; MacMillan et al, 2003a; Stark et al, 2003; Keen et al, 2004).

TNF genes

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

The TNFα gene is located within the class III region of the major histocompatiblity complex (MHC). Therefore, in an HLA-identical sibling HSCT, the recipient and donor genotype will be identical and may equally or additively affect TNF production and HSCT outcome. Initial HSCT studies associated recipient genotype (d3/d3) of the TNFd microsatellite with increased severity of acute GvHD (grades III–IV) in ciclosporin-alone treated HLA-matched sibling HSCT (Middleton et al, 1998). A larger cohort of transplants receiving ciclosporin plus methotrexate (MTX) prophylaxis demonstrated an association of recipient TNFd/d3 genotype with increased mortality (Cavet et al, 1999), and Bogunia-Kubik et al (2003) have associated TNFα and TNFβ genotypes with toxic complications. A Japanese HLA-matched unrelated HSCT study described an association of the TNF-863 and TNF-857 polymorphisms in donors and/or recipients with a higher incidence of GvHD grades III–IV and a lower rate of relapse (Ishikawa et al, 2002), however in HLA-A, -B and -DRB1 matched pairs only GvHD outcome remained statistically significant. Other SNPs around the TNF locus, such as TNFα-238 and TNFβ-252, have also been reported to associate with HSCT-related complications, including GvHD and early death, in a matching unrelated HSCT study (Keen et al, 2004). A polymorphism (196 R/M) in the TNF receptor II gene in HLA-matched unrelated HSCT found that recipients of TNFRII-196R-positive donors had a higher incidence of severe GvHD and a lower rate of relapse than from TNFRII 196 M homozygous donors (Ishikawa et al, 2002). The recipient TNFRII 196R allele was associated with acute GvHD incidence but the TNFRII 196RR genotype in the donor was associated with (increased) incidence of extensive chronic GvHD in an HLA-matched sibling HSCT cohort (Stark et al, 2003).

IL10 gene

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

The SNPs and microsatellites of the IL-10 gene resolve into several conserved haplotypes. Three common haplotypes of the promoter region that lie between 1082 and 592 represent high, intermediate and low (GCC, ATA, ACC) IL-10 producer alleles. The low producer (ACC) haplotype in the recipient was associated with severe acute GvHD grades III–IV in ciclosporin alone (Cavet et al, 1999) and ciclosporin plus MTX-treated (Ishikawa et al, 2002) HLA-matched sibling HSCT cohorts. The intermediate producer IL-10 haplotype (ATA) has recently been confirmed to play a role in both survival and GvHD (severe) in HLA-matched sibling HSCT, where, in this single study, two large cohorts (>400 patients) were analysed (Lin et al, 2003). In a cohort of HLA-mismatched cord blood transplants (Kögler et al, 2002) neither the IL-10 nor the TNFα gene polymorphisms were associated with transplant outcome. This may have been the result of the small size and heterogeneity of the cohort and/or differences in the immunobiology of the cord blood cells. Moreover, the influence of HLA in HLA-mismatched cord blood transplants may overcome other non-HLA genetic factors.

IL-1 gene family

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

HLA-matched sibling transplant studies have demonstrated an association of the IL-1 receptor antagonist variable number tandem repeat (VNTR) (allele 2), which downregulates IL-1 production, in the donor genotype with less severe acute GvHD, and in the recipient genotype with chronic GvHD (Cullup et al, 2001; Rocha et al, 2002). Carriage of allele 2 (donor genotype) in either the VNTR or −889 polymorphisms of IL-1α gene was associated with chronic GvHD (Cullup et al, 2003). A study of paediatric unrelated HSCT found that IL-1α-889 in either donor or recipient was associated with improved survival and decreased transplant-related mortality (TRM), but not with GvHD (MacMillan et al, 2003a).

TGFβ gene

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

A polymorphism (509 C/T) of the TGFβ in the promoter region is associated with variation in plasma concentration of TGF-β (the C allele is associated with higher production) (Grainger et al, 1999), and amino acid substitutions at codons 10 (leu[RIGHTWARDS ARROW]pro) and 25 (arg[RIGHTWARDS ARROW]pro), which alters protein structure. A small study of HLA-identical sibling HSCT cases showed no association of the TGF-β509 polymorphism with either GvHD or other outcomes (Grainger et al, 1999; Cavet et al, 2001). Other studies have shown an influence of the high expression G/G genotype for TGF-β codon 25 with more severe GvHD (Leffell et al, 2001) and a study in 67 paediatric patients showed an association with the TGF-β1 codon 10 polymorphism in the donor genotype and development of aGvHD. TGF-β1 receptor II polymorphism (1167 C/T) genotype in the recipients in the same study was also associated with the development of GvHD (Hattori et al, 2002).

Gene associations with HSCT outcome and interpretation of results

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

The CGPs studied have usually been associated with altered cytokine production in vivo or with transplant-related pathology, and/or been associated with immune dysfunction and autoimmune diseases. Typically, alleles linked with increased expression of pro-inflammatory cytokines, such as TNFα, IL-6 and IFN-γ show protection effects (see Table I). Several problems, however, surround the interpretation of the results of cytokine gene polymorphism analysis and their potential role in HSCT outcome. Furthermore, as more knowledge is gained with regard to the gene maps of some of the cytokine genes, the influence on the polymorphisms in neighbouring genes and on the cytokine response may become more complex. For example, with regard to the TNF locus, a detailed analysis of this microsatellite locus has revealed additional genetic structures, SNPs and insertions/deletions that effectively define subtypes of the two candidate alleles TNFd3 and TNFd4, which have been implicated in the association studies in HSCT (Spink et al, 2004).

In addition, IL-10 appears to possess a dual nature, with both pro-inflammatory and anti-inflammatory properties (Mocellin et al, 2003). Given the differences in modality and clinical protocols used between HSCT patient groups, it is not unrealistic to consider that the influence of IL-10 and IL-10 genotype, for example, on HSCT outcome may be dependent on the clinical protocols used in a particular cohort under study.

HLA association

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

In HLA-matched sibling HSCT some HLA antigens, such as HLA-A3, are associated with a higher and DR1 with a lower risk of GvHD. These associations may represent HLA types best able to present specific antigens relevant to disease processes. Alternatively, the effect on GvHD may reflect class III region TNF polymorphisms forming an extended haplotype with the HLA class I and class II region. Determining what precisely occurs at this locus is therefore complex. In the unrelated HSCT setting, the role of HLA will be of a paramount importance in the interpretation of non-HLA genetic data. High resolution tissue typing and standardization of results is necessary across HSCT centres for comparative studies. GvHD increases proportionally with the degree of HLA class I and II disparity between the patient and the donor. Mismatching for HLA-C alleles may increase the risk of graft failure, GvHD and mortality. Disparities between HLA sequence polymorphisms detected by serology are termed antigen mismatches; those identified only by DNA-based typing are termed allele mismatches. The risk of mortality after unrelated HSCT transplants is increased by mismatches at a single allele at HLA -A -B -C -DRB1, DQB1 and recently at DPB1 (Zino et al, 2004). The significance of these mismatches must be taken into account prior to further analysis of the data for the role of non-HLA immunogenetics in the unrelated HSCT setting.

Population differences in gene frequencies

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

In vivo disease association may not necessarily correlate with in vitro cytokine expression or production. This could be the result of genetic variation in allele frequencies between different ethnic populations resulting in different associations being found. Therefore, comparisons between populations are difficult unless local population allele frequency is simultaneously assessed and taken into account. For example, the IL-10 GCC haplotype in Japan is of a very low frequency compared with Europe and therefore the influence of the IL-10 genotype may be different in different HSCT cohorts from Japan and Europe.

Different transplant procedures and number of patients studied

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

Analysis of the complex data emerging on the role of non-HLA immunogenetics in HSCT outcome is compounded by a number of factors, including the heterogeneity of the diagnoses and clinical state of the recipients, GvHD prophylaxis regimes, conditioning strategies and strategies that aim to prevent bacterial or opportunistic infections. Most of the research has been carried out within the HLA-matched HSCT setting. Because of the heterogeneity of cohorts analysed and the low frequency of some polymorphisms in the population, larger studies are now needed, taking into account, multivariate analysis other disease- and transplant-related factors in both HLA-matched sibling and unrelated HSCT.

Minor histocompatibility antigens and HSCT outcome

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

GvHD occurring after HLA-matched sibling HSCT is initiated by T cells recognizing mHag: mHags are peptides derived from intracellular proteins of restricted polymorphisms coded by autosomal or Y chromosome genes and presented by HLA molecules (reviewed in Goulmy, 1996). T-cell clones recognizing mHags were initially isolated after bone marrow transplantation in patients that developed GvHD or graft rejection (Goulmy et al, 1983). The male-specific mHags encoded by the Y chromosome have been shown to be involved in HLA-matched, sex mismatched HSCT (Goulmy et al, 1977, 1980). The first H-Y gene identified, which encoded HLA B7 and HLA-A2 restricted mHag, was SMCY (Wang et al, 1995; Meadows et al, 1997). A number of other mHags have now been identified. The DFFRY and UTY genes have also been identified as coding for human MHC class I-restricted H-Y antigens. Human H-Y antigens therefore are encoded by multiple Y-specific genes with differences of only 1–4 amino acids occurring between the male-specific mHags and their X homologues. The human mHags currently identified tend to be HLA class I restricted, but recently the first human HLA class II-restricted sex-linked mHag involved in GvHD was characterized (Vogt et al, 2002). The mHag was recognized by a CD4+ cytotoxic T-cell clone isolated post-transplant from a male patient who developed grade III–IV GvHD after transplantation from a female genotypical identical donor. More recently, Randolph et al (2004) studied the contribution of donor/patient sex on the risk of disease relapse and/or GvHD in 3238 patients who underwent HLA-identical sibling HSCT for haematological malignancies. This study showed that male recipients of female transplants had the lowest risk of relapse and greatest risk of GvHD. The data suggested that mHag encoded or regulated by genes in the Y chromosome may contribute to graft versus leukaemia effects against myeloid and lymphoid leukaemia after female to male HSCT. Another study (Miklos et al, 2004) has also demonstrated that mHag responses elicited in male recipients of female transplants can also involve B cells as well as T cells with detectable antibody responses to recombinant DBY protein. The tissue expression of some mHag (e.g. HA-1 and HA-2) is limited to the haematopoietic system whereas other mHag, as discussed (e.g. H-Y, HA-3), are ubiquitously expressed on normal tissues (de Bueger et al, 1992). Mismatches between patient and donor for HA-1, HA-2, 4 and 5 are associated with increased GvHD incidence (Goulmy, 1996). The precise characterization of the peptide sequence of haematopoietic tissue-restricted or cancer cell-restricted mHag make them ideal targets for immunotherapy using either ex vivo generated mHag HA-1- and HA-2-specific cytotoxic T lymphocytes or donor lymphocyte infusions (Mutis et al, 1999; Marijt et al, 2003). HA-1- and/or HA-2-positive patients with relapse after allogeneic HSCT have recently been treated with donor lymphocyte infusions from their mHag HA-1- and/or HA-2-negative donors. The subsequent emergence of HA-1- and HA-2-specific CD8+ T cells in the peripheral blood of the recipients led to complete remission of the leukaemia and 100% donor chimaerism (Marijt et al, 2003). mHag HA-1 is also expressed on epithelial cancer cells and not on normal epithelial cells, giving rise to the concept of the use of mHag in more diverse cancer therapies (Klein et al, 2002).

Other non-HLA-encoded genes implicated in HSCT related complications

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

Table II lists other non-HLA gene polymorphisms, implicated in host defence, the immune system and metabolism of drugs that have been associated with HSCT outcome.

Table II.  Non-HLA gene polymorphisms of recipients and donors associated with allogeneic HSCT outcome.
Genes associated withAlleles or point muationsProposed functionAssociation of patient genotype with outcomes after HSCTAssociation of donor genotype with outcomes after HSCT
  1. MPO, myeloperoxidase, an enzyme found primarily in the lysomes of neutrophils. A single base substitution (G[RIGHTWARDS ARROW]A) in the promoter region of the MPO gene (−463) decreases expression and alters the binding site for the transcription factor.

  2. FcγRIIa, Fcγ receptor, polymorphisms of the receptor affect receptor affinity and specificity.

  3. FcγRIIIb, Fcγ receptor HNA1a and HNA1b, isoforms affect different ligand binding of antibodies.

  4. OER, oestrogen receptor, a member of the steroid/thyroid hormone superfamily of nuclear receptors, has two isoforms, ERα and ERβ. ERα is a ligand-activated transcription factor composed of several domains for hormone binding, DNA binding and activation of transcription. ERα is a mediator in the signal transduction pathways and polymorphisms in the gene for ERα may impair ERα production.

  5. CYP2B6 is part of the P450 gene family and is associated with drug and steroid metabolism.

  6. MBL, mannose-binding lectin is a member of the collectin family that binds carbohydrate moieties in bacterial viral, fungal and protozoal pathogens independent of antibody. It directly or via complement activation opsonizes pathogens for phagocytosis. MBL is encoded by the MBL2 gene on chromosome 10 and five single nucleotide polymorphisms influencing serum. MBL levels have been identified and studied with respect to risk of major infection following allogeneic HSCT (Mullighan et al, 2002). Three haplotypes, HYA, LYA and LXA, are associated with high, intermediate and low levels of MBL respectively.

  7. VDR, vitamin D receptor, like other receptors for steroid hormones and thyroid hormones, has hormone binding and DNA binding domains. VDR complexes that have an intracellular receptor retinoid X-receptor, which binds to DNA causing activation or suppression of transcription, control not only calcium absorption but also the growth and differentiation of many types of cells. Polymorphisms within the VDR gene may influence vitamin D metabolism and subsequent immune dysregulation.

  8. MTHFR, 5,10 methylenetetrahydrofolatereductase converts 5, 10 methylenetetrahydrofolate to 5, 10 methyltetrahydrofolate. The common polymorphism L677T results in reduced activity of the enzyme, potentially exacerbating the effect of methotrexate, an antifolate chemotherapeutic drug.

Immune system
MPO (Rocha et al, 2002)AG/AADecreased intracellular concentration and decreased bactericidal activity Increased bacterial infection Increased risk of non-leukaemic death
FcγRIIa (Rocha et al, 2002)R-131R131 allelic binds IgG2 poorlyIncreased first overall infections 
FcγRIIIb (Rocha et al, 2002)HNA1a/HNA1aIt bears the human neutrophil antigen (HNA) polymorphism implicated in alloimmune and autoimmune neutropenias Delayed neutrophil recovery Severe infection Increased risk of non-leukaemic death
HNA1b/HNA1b Increased transplantation-related mortality rates 
HNA1a/HNA1b  Quick neutrophil recovery
MBL (Mullighan et al, 2002)HYA haplotypeHigh producing MBL haplotype Polymorphisms result in disrupting MBL peptides on functional polymers resulting in reduction in serum levels of functional MBLDecreased infectionDecreased infection
MBL2 coding mutationsIndividuals heterozygous or homozygous for the mutations have reduced or absent concentrations of MBL in serum and is an important risk factor for infection in situations where the immune response is already compromisedIncreased risk of major infectionIncreased risk of major infection
VDRVDR apalSNP in strong linkage with the other intron8/exon9 polymorphisms in the VDR gene (see below)See belowSee below
VDR (Middleton et al, 2002; Rocha et al, 2003)VDR taq1, tT or TTVDR (t) facilitate strong Th1 cell mediated immune response whereas VDR (T) possibly favour a Th2 cell lineage for newly-activated CD4+ cellsIncreased risk of acute GvHD (III–IV)Increased TRM
OERα (Middleton et al, 2003)XbaI (IVSI-401c allele) (PX haplotype)Proposed to affect production of estrogen receptor, which mediates the many effects of estrogens on the immune system and its developmentXbaI SNP (IVS1 – 401C allele) with aGvHD and reduced survival 
NOD2/CARD15 (Holler et al, 2004)SNP, 8, 12 and 13Intracellular sensor for muramyl-dipeptide (MDP) inducing NFκB and subsequent inflammatory cascadesMutated SNPs 8,12, and 13, with increased risk of GvHDIncreased risk of severe GvHD and TRM
Drug metabolism
MTHFR (Ulrich et al, 2001; Rocha et al, 2003)677 CT/TTPolymorphism leads to a thermolabile variant of the enzyme and it is associated with reduced enzyme activity (30% for TT and 60% for CT compared with the wild type (CC) activity) and increased homocysteine levelsMucositis Delayed platelet recovery Acute GvHD (II–IV) 
CYP2B6 (Rocha et al, 2003)*2A CT/TT *4 AG/GG *6 GT/TTLower P450 enzyme expression or level and higher accumulation of cytotoxic metabolitesHaemorrhagic cystitis Mucositis VODHaemorrhagic cystitis VOD

Genes implicated in host defence and the immune system

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

Other non-HLA encoded genes have been recently implicated not only in GvHD, but also in TRM, infectious episodes and other outcomes in HLA-matched sibling HSCT (Middleton et al, 2002, 2003; Mullighan et al, 2002; Rocha et al, 2002). The steroid hormone receptor supergene family includes the oestrogen receptor and the vitamin D receptor (VDR), both have marked effects on the development of the immune system and variations in VDR are associated with autoimmune and immune dysfunctional diseases. Vitamin D analogues can prolong graft survival and prevent GvHD in animal studies. Polymorphism in the VDR intron 8 region (Middleton et al, 2002, 2003), and in intron 1 of the oestrogen receptor alpha (ERα) genes have been associated with both occurrence of GvHD, post-transplant infection and likelihood of survival following allogeneic HSCT (Middleton et al, 2002, 2003; Rocha et al, 2003). Donor and recipient genotype in genes that regulate the host response to microorganisms [myeloperoxidase (MPO), mannose binding lectin (MBL) and Fcγ receptors (FcγRIIa, IIIa, IIIb)] have also been associated with infections after bone marrow transplantation (Mullighan et al 2002, Rocha et al 2002). The incidence of first infections post-transplant has been associated with the R-131 allele in the patient FcγRIIa genotype and occurrence of severe bacterial infections increased when the MPO donor genotype was AG or AA compared to the CC wild genotype. Transplant related mortality (TRM) was influenced by the FcγRIIIb genotype and the donor MPO genotype (see Table II). These studies further define and improve understanding of the mechanisms involved in host defence against infection during HSCT (Mullighan et al 2002, Rocha et al 2002).

As previously discussed, the inflammatory response following the activation of inflammatory cells by bacterial compounds is a further important player in the induction of GvHD and severe complications following HSCT. While experimental evidence for a major role of susceptibility to endotoxin in GvHD is overwhelming, only a few studies have addressed this question in humans. Polymorphisms for Toll like receptors TLR4 have been discussed as risk factors for GvHD and infections (Lorenz et al, 2001). In addition, polymorphisms of the intracytoplasmatic sensor to muramyl-dipeptide, NOD2/CARD15, which were identified as the first inflammatory bowel disease genes, have recently been tested in patients and donors receiving allogeneic HSCT (Holler et al, 2004). In two cohorts of patients, in a total of 270 HSCT patients/donor pairs, NOD2/CARD15 polymorphisms that are associated with a diminished antibacterial nuclear factor κB (NFκB) response increased the risk of severe GvHD grade III/IV and subsequently in overall transplantation related mortality. In fact, the presence of the patient or donor NOD2/CARD15 polymorphisms increased the risk of the occurrence of severe acute GvHD (grade III–IV) to 2·7 to 4·6 times in both cohorts compared with patients/recipients with the unmutated genotype. Therefore the risk of mortality related to transplantation increased 2·8 to 3·1 times more (from 23 to 46%) in donor/patients who carried the mutant polymorphisms (Holler et al, 2004).

Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

Recently, polymorphisms of genes that interfere with the metabolism of drugs used in GvHD prophylaxis (Ulrich et al, 2001) or conditioning regimes have been associated with toxicities, platelet recovery, GvHD and survival after HSCT (Ulrich et al, 2001; Rocha et al, 2003). More than a dozen polymorphisms have been described in the methylenetetrahydrofolate-reductase (MTHFR) gene (Evans, 2002) that codes for the enzyme MTHFR, which has an important role in the folate pathway and therefore in the metabolism of MTX used in GvHD prophylaxis. Of these polymorphisms, C677T has been associated with altered phenotypes and adverse MTX events (Evans, 2002). It leads to a thermolabile variant of the MTHFR enzyme with decreased enzyme activity, and subsequent increased plasma homocysteine levels that may be important in mediating the gastrointestinal toxicity from MTX (Haagsma et al, 1991). The homozygous C677T variant, with approximately 30% of wild type activity, is present in approximately 8–10% of the general population. Heterozygotes have about 60% activity and comprise approximately 40% of the population. Recipient polymorphism of the MTHFR gene in position C677T was found to be associated with a higher incidence of mucositis and delayed platelet recovery after HSCT (Ulrich et al, 2001). More recently, in a multivariate analysis including other clinical factors, the recipient genotype (CT or TT) was also associated with the incidence of acute GvHD (Rocha et al, 2003). Interestingly, recipient polymorphisms of genes of the P450 cytochrome family (CYP2B6) that interfere with the activation of cyclophosphamide, frequently used in conditioning regimens, have been associated with mucositis, haemorrhagic cystitis and veno-occlusive disease of the liver (Rocha et al, 2003) (Table II).

Clinical relevance in the future management of HSCT

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

Developing a diagnostic or prognostic risk score and extending the predictive power of genetic polymorphisms is the major aim of ongoing research. Large cohorts of HLA-matched and unrelated HSCT are currently being compiled to fully investigate and test the hypothesis that certain non-HLA gene polymorphisms predict transplant-related complications. The combined analysis of TNFd3/d3, IL-10, IFNγ (intron 1;(3,3), IL-6−174 GG, IL-1Ra, suggest that a risk index for GvHD could be developed (Dickinson et al, 2001) alongside clinical risk factors such as gender, age, CMV status and minor histocompatibility mismatches. To date IL-6−174 and IL-1Ra appear the most robust risk factors, with several independent confirmatory reports of their potential role in predicting acute and chronic GvHD independent of prophylaxis and transplant type (Cavet et al, 1999; Sociéet al, 2001). Further research into the possible role of pharmacogenomics (Leather, 2004) in determining outcome may allow risk prediction to tailor prophylaxis and therapy for GvHD, prophylaxis for infections and conditioning regimes on a disease-specific or individual patient basis. Risk-adapted selection of recipients and donors or selection of strategies for prophylaxis and treatment of complications may result from these risk indices and thus hopefully contribute to individualized and improved patient care in the future. Furthermore, in the future application of DNA chips evaluation of multiple inflammatory SNPs may identify risk clusters predicting specific complications.

Further research in the future on the influence of killer-inhibiting receptor (KIR) genes (Giebel et al, 2003) and MHC (class I chain MIC genes (Collins, 2004) will further increase the knowledge base for the understanding of complex genetics in allogeneic haematopoietic stem cell transplants.

Acknowledgements

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References

The research is supported by European Framework V grants (Contract No: QLRI-CT-2000–0010 EUROBANK and QLK3-CT-2002–01936 TRANSEUROPE). AD, as co-ordinator of the EC projects, wishes to acknowledge all other partners who contribute to EUROBANK; namely Professor Eliane Gluckman, INSERM Paris, Professor D Charron and co-workers (Prof. A Toubert; Dr E Clave; Dr P Loiseau), HLA et Medecine, University of Paris; Professor A Madrigal, Dr T Dodi, C Roberts, Anthony Nolan Research Institute London UK; Professor P Wernet, Dr G Kögler, Dr M Uhrberg, Heinrich Heine University Düsseldorf; Professor E Goulmy, Dr B Wieles, Leiden University Medical Centre, Leiden, The Netherlands; Professor H-J Kolb, Ludwig Maximillian University, Munich; Dr M Weber, GSF, Munich, Germany; Professor H Greinix, University of Vienna.

The Newcastle team was also supported by grants from the Tyneside Leukaemia Research Association and Leukaemia Research Fund. The Newcastle team wish also to acknowledge Leigh Keen and Caroline Spink (Bristol), Gail Stark, Hannah Cullup and Annette Neylon all for ‘helpful discussions’.

Work undertaken by the Paris group has been supported by Assistance Publique-Hopitaux de Paris, IFR Saint Louis, Association pour la recherche sur les transplantations medullaires (ARTM) and Fundaçao de Amparo à Pesquisa Do Estado de sao Paulo (FAPESP), Brazil and acknowledgements go to Pr MA Zago, Cellular Therapy and Immunogenetics Laboratory, Ribeirao Preto, Sao Paulo, Brazil.

The Regensburg team was also supported by the Broad Medical Research Programme (BMRP, grant to GR) and the BMBF Competence Network for Inflammatory Bowel Diseases and acknowledge G. Eissner, J. Hahn, H. Bremm, G. Rogler, H. Herfarth, J. Brenmoehl and U. Schulz for collection of samples, ‘helpful discussion’ and NOD2/CARD15 analyses.

References

  1. Top of page
  2. Summary
  3. Influence of cytokines and their gene polymorphisms on GvHD and post-transplant complications
  4. Cytokine gene polymorphisms
  5. TNF genes
  6. IL10 gene
  7. IL-6 gene
  8. IFNγ
  9. IL-1 gene family
  10. IL-2 gene family
  11. TGFβ gene
  12. Gene associations with HSCT outcome and interpretation of results
  13. HLA association
  14. Population differences in gene frequencies
  15. Different transplant procedures and number of patients studied
  16. Minor histocompatibility antigens and HSCT outcome
  17. Other non-HLA-encoded genes implicated in HSCT related complications
  18. Genes implicated in host defence and the immune system
  19. Genes implicated in metabolism of drugs used in preparative regimens and in GvHD prophylaxis
  20. Clinical relevance in the future management of HSCT
  21. Acknowledgements
  22. References
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