Current and future aspects of HLA in transfusion medicine, transplantation and cellular therapy

Authors


  • 4D-S29-01

Prof. Dr. Dr. h.c. Wolfgang R. Mayr, Universitätsklinik für Blutgruppenserologie und Transfusionsmedizin, Währinger Gürtel 18-20, A-1090 Wien/Österreich
E-mail: wolfgang.mayr@meduniwien.ac.at

Abstract

The current and future role of gene products of the HLA system in transfusion medicine, transplantation and cellular therapy is briefly discussed.

The HLA complex is located on a chromosomal segment on the short arm of chromosome 6 (6p21·31). It is also referred to as the human major histocompatibility complex – MHC, a cluster of genes encoding molecules that have immunological functions and govern histocompatibility. Such a MHC has been found in all vertebrates studied so far. In humans, it is arranged in two chromosomal regions named HLA class I and HLA class II; the chromosomal region in between those two has been designated ‘HLA class III’ [see e.g. 1]. A complete gene map for a single, artificial HLA haplotype has been assembled, and its contiguous nucleotide sequence has been determined. In this refined analysis, the HLA complex has turned out to be one of the most gene-dense regions of the human genome, as it contains at least 300 expressed loci.

Transfusion medicine

The HLA system is relevant for the following problems [see e.g. 2]:

  • 1 Immunization against HLA gene products carried by cells transmitted via transfusions (for primary immunizations, HLA class II antigens seem to be of greater importance than class I antigens, while booster immunizations can be induced by HLA class I).
  • 2 Platelet refractoriness mainly induced by antibodies against HLA class I gene products, but also by HPA antibodies.
  • 3 Febrile non-haemolytic transfusion reactions (FNHTR) often caused by antibodies against HLA class I gene products, but also by antibodies against HNA.
  • 4 Transfusion-associated acute lung injury (TRALI) attributable to antibodies against HLA (class I and class II) and HNA gene products [3].
  • 5 Transfusion-associated graft-versus-host disease (TA-GvHD) induced by the transfusion of HLA-compatible, immunologically responsive T lymphocytes [4].
  • 6 Haemolytic transfusion reactions: some erythrocyte antigens are governed by loci of the HLA system. The antigens of the Bg system are HLA class I antigens expressed on red blood cells, while the antigens of the systems Chido and Rodgers are carried by C4 molecules (coded for by the ‘HLA class III’ region). Antibodies against these factors might destroy a small proportion of antigen positive cells; they have, however, not been implicated in severe haemolytic reactions.

In future, the significance of HLA for transfusion medicine will not increase as the connected problems can be handled easily: avoidance of the induction of HLA antibodies and of FNHTR by leukodepletion, avoidance of TRALI by HLA and HNA antibody negative donors and of TA-GvHD by irradiation of the products.

Transplantation

Solid organ transplantation

In kidney transplantation, compatibility in HLA class II and HLA class I antigens increases the survival of grafted organs (if the recipient carries no antibodies against AB0 and HLA class I antigens of the donor). This effect of the HLA system is particularly seen in cases of HLA-immunized recipients and in retransplantation [5]. Similar criteria apply for the transplantation of pancreas. In heart, lung or liver transplantation, it is usually not possible to select according the HLA compatibility so that only AB0 compatibility is respected in most cases.

Stem cell transplantation [6]

In the therapy with adult stem cells, a genotypic HLA class I and class II identity between donor and recipient for the loci HLA-A, -B, -C, -DR (DRB1) and -DQ is optimal. In siblings, this situation is found in 25% of the cases. If an unrelated individual acts as donors, its HLA-A,B,C,DR,DQ genotype has to be determined by sequencing the respective alleles (high resolution genotyping). As a result of the enormous HLA polymorphism, the chance to find two HLA identical unrelated individuals is extremely low. For this reason, a huge number of potential donors willing to give their stem cells for a patient in need have been listed in national and international registries; in March 2010, more than 13·7 millions of donors are registered in Bone Marrow Donors Worldwide (http://www.bmdw.org). If no identical donor is available, single mismatches in HLA-DQ or -DR (class II) seem to be less deleterious than single mismatches in HLA-A, -B or -C (class I). The detailed analysis of mismatched donor–recipient pairs gave some hints for permissible mismatches in Japanese; a general use of such permissible mismatches, however, is not possible for the moment. The influence of HLA-DPB1 matches or mismatches in HLA-A,B,C,DR,DQ matched pairs has been investigated: HLA-DPB1 mismatching is accompanied by an increased risk of graft-versus-host disease, but by a lower risk of relapse.

For the transplantation of umbilical cord blood stem cells (UCB), HLA matching seems to be less important owing to the relative low number of mature T cells in cord blood. In such cases, only the following HLA determinants are considered: HLA-A and -B typed at antigen level (low resolution genotyping) and HLA-DRB1 typed at allele level (sequencing = high resolution genotyping). Up to two mismatches are acceptable; better HLA matching and higher cell doses decrease the rate of transplant-related mortality. A large number of cord blood units are banked and kept frozen in different centres; the number of UCB units registered by Bone Marrow Donors Worldwide in March 2010 amounts to more than 410 000. If the number of cells in the UCB preparation is too low, a double UCB transplantation can be envisaged. In these cases, HLA class I matching (especially HLA-B) is associated with a faster engraftment of neutrophil granulocytes. It is also interesting to remark that in most cases, after the engraftment, only one of the transplanted cell populations is demonstrable in the recipient.

It is probable that another genetic system that is not genetically linked to HLA influences the outcome of stem cell transplantations: the Killer cell Immunoglobulin Receptor (KIR) locus situated on chromosome 19 that encodes activating and inhibitory receptors expressed mainly by NK cells. The ligands of some KIRs are MHC class I molecules (HLA-A3, HLA-Bw4, group C1 = HLA-C gene products with asparagine at position 80, or group C2 = HLA-C gene products with lysine at position 80). The KIR locus is highly diverse: KIR haplotypes vary in their content of genes, and the single genes show an allelic polymorphism. The first clear-cut influence of KIR on stem cell transplantation could be shown in patients with acute myeloid leukaemia who received T-cell-depleted stem cells from HLA-haplotype-mismatched family members: the patients showing a KIR ligand incompatibility in graft-versus-host direction had no relapse after 5 years (n = 34), while 75% of the patients without such incompatibility relapsed after 5 years (n = 58; P < 0·0008). Further investigations concerning the significance of KIRs, however, gave no unambiguous results, so that it is not possible for the moment to include the typing of the KIR polymorphism in the donor selection in stem cell transplantation. The differences observed in the various studies are probably attributable to a series of reasons: disease of the patient, conditioning regimen, type of stem cell graft, study population, expression of KIR molecules on the NK cell surface, etc.

Cellular therapy

In cellular therapy (with dendritic cells, NK cells, cytotoxic T lymphocytes [7]), regenerative medicine and gene medicine, mainly autologous cells are used. If allogeneic cells are applied, HLA identity or tolerance of the recipient to the foreign HLA gene products should be achieved.

If cells are loaded with peptide antigens (e.g. tumour antigens), the structure of these antigens must be selected in such a way that the peptides can be presented by the HLA antigens of the activated cells [8].

The fit between HLA gene products and peptide antigens must also be taken into consideration when designing immunogens used in vaccinations (presentation of antigens by HLA gene products during the immune response).

The analysis of the expression of HLA antigens in tumour cells can also give some prognoses for the progression of the tumour as melanoma cells with a high HLA class I expression frequently show a regression of their growth [9].

The importance of HLA in transplantation will increase owing to a better understanding of permissible incompatibilities and of the influence of other genetic systems, e.g. KIR; furthermore, a better knowledge of the function of the HLA gene products will be helpful for the selection of cells and of antigens for therapeutic purposes in malignant diseases and in vaccination.

Disclosures

None.

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