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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

According to the humoral theory of transplantation, antibodies cause allograft rejection. Publications are cited showing that antibodies: (1) cause hyperacute kidney rejection, (2) lead to C4d deposits associated with early kidney graft failures, (3) are a good indicator of presensitization leading to early acute rejections, (4) were present in 96% of 826 patients who rejected a kidney graft, (5) are associated with chronic rejection in 33 studies of kidney, heart, lung and liver grafts, and (6) in three studies, appeared in the circulation BEFORE evidence of bronchiolitis obliterans in lung transplants, and BEFORE kidney rejection. In addition, a prospective cooperative study of 1629 patients in 24 centers demonstrated that antibodies foretold subsequent failures after a follow-up period of 6 months (p = 0.05). The specificity of antibodies detected in the serum of rejecting patients were often not donor specific, presumably because they were absorbed by the rejecting organ.

If the humoral theory is accepted, even provisionally, transplanted patients who have antibodies could be treated with immunosuppression until the antibodies disappear to determine whether chronic rejection can be blocked. If successful, in patients who do not have antibodies, immunosuppression could be reduced until antibodies appear.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

In the 1950s, the important question of the day was, ‘are grafts rejected by antibodies (humoral theory) or by cells?’ We do not hear much about this debate today, because for the past 40 years it has almost been an accepted fact that the cellular theory is correct. This conclusion was reached by the sheer force of one man's personality, for few would take exception to the overpowering dogma of Sir Peter Medawar. Another possible reason we do not hear much of the debate today is that we now ‘KNOW’ that BOTH humoral and cellular mechanisms are involved in rejection. But is this so?

Of course, antibodies are produced by cells, and in this sense all rejections are cellular. The critical difference between the two theories is: (a) are grafts destroyed by the action of antibodies or (b) by direct cellular cytotoxicity, as occurs with cytotoxic T cells, NK cells, or DTH reactions.

I will review the accumulating evidence that HLA antibodies can directly cause allograft rejection in humans. This is not intended to be a ‘balanced’ review, and assumes that the reader has had sufficient exposure to the abundant literature showing that rejection is produced by cells, such as DTH reactions and tubulitis lesions produced by T cells in kidney transplants. Various current immunosuppressive treatments may have successfully suppressed cellular immunity, leaving humoral reactivity to be dealt with in the remaining patients.

Gorer first showed that various antibodies in mice could be detected against the H-2 histocompatibility locus antigens (1). Based on these studies, a large-scale international effort with extensive collaboration in international workshops resulted in the discovery of antibodies to HLA antigens in humans. Thus, acceptance of the humoral theory led to uncovering the antigens against which allograft reaction is directed. Admittedly, some pursued this line of research purely as a scientific endeavor, but my work was based from the outset on the idea that the antibodies are the visible indicators of the transplantation antigens, and the means by which we can get to the root of the problem.

HLA antibodies instantly kill a kidney: hyperacute rejection

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

The awesome power of HLA antibodies became apparent with the finding that when a kidney graft is transplanted into a patient with HLA antibodies directed against antigens of the kidney, the kidney is killed immediately (2). Thus, an entire organ such as a kidney could be destroyed by antibodies within minutes. Occasionally, not often, HLA antibodies directed against B cells produce hyperacute rejection (3). The particular susceptibility of the lung to antibody-mediated hyperacute rejections is apparent from recent experiences (4,5). Hearts are also susceptible to hyperacute rejection (6).

When the kidney is rejected minutes before closure of the incision, hyperacute rejection is obvious. However, we called attention to hidden hyperacute rejection when the kidney is rejected after the wound is closed, and the kidney never functions. In 1987, the primary nonfunction rate of the first cadaver grafts was 8% in 7788 first grafts, 14% in 1471 second grafts, and 20% in 224 third grafts (7). This large difference in primary nonfunction rate was almost certainly the result of hidden hyperacute rejection following sensitization by graft rejection. Today, with improved crossmatching methods, this large difference in primary nonfunction has been eliminated, and graft survival in first and regrafted patients is virtually identical (8).

The extraordinary power of antibodies is shown when high-titered HLA antibodies transfused intravenously can even kill a patient within hours. The phenomenon of transfusion-related acute lung injury (TRALI) produced by sera from highly immunized pregnant women was first described in 1970 (9), and reviewed in 1985 (10) and 2001 (11).

State of preimmunization is detected by HLA antibodies

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

When patients are immunized by the process of rejecting an allograft, the only current practical way to detect this state of immunization is by a humoral (not cellular) test: that is, examining patients for the presence of HLA antibodies. Such antibodies are found in pregnant women, patients immunized by transfusions, those immunized by rejection of a previous graft, and patients with cadaveric venous and arterial allografts (12). Proof that a humoral test for sensitization is effective was first provided by survival curves in patients classified according to the presence or absence of cytotoxic antibodies (13) (Figure 1). Patients sensitized before transplantation had lower graft survival rates than nonsensitized patients. Moreover, this effect was even more marked in patients who had previously rejected a transplant. In the intervening 30 years, many publications have reconfirmed the fact that antibodies, as a measure of presensitization, are important for kidney (14–26), heart (27–30), liver (31–34) and lung (5) transplants.

image

Figure 1. First demonstration that patients classified by their panel reactive antibody (PRA) as having HLA antibodies BEFORE transplantation would have lower graft survival rates than those without antibodies (13). The effect is greater in second transplants than in first grafts. It is probable that the antibodies themselves produce graft destruction early after transplantation.

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HLA antibodies are associated with acute early rejection

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

For many years, antibodies were sought in biopsies taken during acute rejections, searching by immunofluorescence for IgG or IgM antibodies, generally to no avail. A major break occurred in 1993 when Feucht demonstrated that an end-product of complement C4d could be demonstrated in peri-tubular capillaries (35). Feucht showed C4d deposits in 51 of 93 dysfunctional grafts. Among patients with c4d, 1-year survival was 57% compared with 90% in those without C4d. Eight years later the same group provided convincing proof of antibodies producing early graft failures (36). They showed that presence of C4d in 117 grafts led to significantly lower graft survival than in 101 grafts without C4d (p = 0.0001) (Figure 2). Antibodies to lymphoblastoid cell lines of the donor DR type were found together with C4d in 14 of 18 patients. Among those patients without antibodies, 11 of 30 had C4d (p = 0.008), suggesting that C4d detection was a more sensitive indicator of antibodies than antibody detection in the circulation.

image

Figure 2. Evidence that early detection of C4d in biopsies is associated with early graft failure (37). The effect of antibodies occurs in the early post-transplantation period.

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A flurry of recent publications by the Munich group (37,38), Boston group (39–43), Vienna group (44–47), Basel group (48) and the Vancouver group (49) has reconfirmed the association of antibody detected with C4d staining in early as well as late failure.

HLA antibodies are associated with chronic rejection

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

Chronic rejection is currently recognized universally as the main transplantation problem. The term ‘chronic rejection’ may have become too loosely defined, and Halloran has proposed a new nomenclature (50,51). However, because this review deals with older studies for which more precise definitions cannot be substituted, we will use the term chronic rejection in the old sense, with special reference to failure resulting from immunologic rejection.

HLA antibodies found AFTER transplantation were first associated with failures in 1968 (52) and 1970 (53). Antibodies to DR were shown to appear after rejection of grafts in 1978 (54), and were studied in a series of patients post-transplantation (55).

In 2000, we reviewed 23 publications in which the presence of HLA antibodies was associated with acute and chronic rejection (56). There were 12 studies of antibodies in post kidney transplant patients (19,57–68). In all the studies, there was a statistically significant correlation of antibodies with acute rejection, chronic rejection, or graft survival. Similarly, there were five studies of heart transplant patients showing that patients with antibodies had lower graft survival rates than those without antibodies (59,69–72). Three studies of lung transplants (73–75), one of liver transplants (76), and two of cornea grafts (77,78) also showed that graft survival was lower in patients with antibodies than in those without antibodies.

Since publication of this review, 10 further papers have been published that show the same type of association for kidneys (17,79–83), kidney-pancreas (84), heart (30), and lungs (85,86).

HLA antibodies are present after almost all kidney failures

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

If HLA antibodies cause graft failure they should be found in the serum of all patients who reject a graft. Our first studies of kidney transplant patients following graft rejection showed 54% had antibodies (52). After the identification of Class II antibodies (54), the percentage of patients with antibodies rose to 72% (55). With further improvements in sensitivity, 82% of patients rejecting a graft had antibodies (87). Following the introduction of the more sensitive flow cytometry tests, Harmer found that 95% of 100 patients studied had antibodies (88). We recently compiled the test results of 826 patients from five different transplant centers who had rejected their transplants (89). Approximately 90% of the patients tested by the AHG enhanced cytotoxicity test for antibodies had antibodies, and when those patients who did not have antibodies were retested by ELISA or flow cytometry tests, the percentage of patients with antibodies rose to approximately 96%. Thus, it is certain that almost all patients who reject a transplant have HLA antibodies. I am not aware of comparable studies in which, for example, 100 patients rejecting a graft have all been shown to have cellular immunity. Although this does not definitively prove a causal relationship for antibodies, it is a result that would be anticipated if the humoral theory is correct. It could, however, be argued that the antibodies were the result of rejection and not the cause of rejection. Evidence to the contrary is given in the next section.

HLA antibodies precede kidney rejection

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

If HLA antibodies cause chronic rejection they should be found BEFORE graft rejection. Development of HLA antibodies preceded the development of bronchiolitis obliterans in 10 of 15 patients. Among the 12 patients who did not develop HLA antibodies, none developed bronchiolitis obliterans (p < 0.001; 75). The temporal relationship strongly indicates that antibodies were responsible for development of bronchiolitis obliterans. In a study of 76 nonsensitized renal transplant recipients, among those who developed antibodies, 11 of 12 patients (92%) lost their grafts, whereas only 11% of 64 patients lost their grafts if they did not produce post-transplant antibodies (p < 0.001; 81). Thus, antibodies were predictive of chronic rejection and were found BEFORE graft failures. In a similar study of 150 renal transplant patients, 25% had antibodies, and among those who had antibodies six had graft failure 3 years later, whereas only one patient who did not have antibodies failed (p < 0.009; 90).

The clearest evidence that antibodies PRECEDE rejection is provided by the studies of Lee (91) (Figure 3). Over a period of 8 years, Lee tested his patients annually for development of antibodies. In the subset of 14 patients who did not have antibodies before transplantation shown in Figure 3, antibodies appeared in all cases before the graft failure. In many instances, years had elapsed between antibody appearance and graft rejection. This suggests that injury produced by antibodies takes a variable and sometimes a considerable amount of time before its action finally manifests.

image

Figure 3. Annual tests for antibodies were carried out on 14 patients who did not have any pretransplant antibodies (91). Chronic rejection and failure after transplantation often occurred many years AFTER the appearance of antibodies.

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In a cooperative prospective chronic rejection study involving 24 international centers, 1629 patients with functioning allografts, who did not have antibodies when they were transplanted, were examined for de novo HLA antibodies. Subsequently, approximately 6 months later, centers were asked to report on patients whose grafts had failed since the time of testing. Of 212 patients who developed antibodies, 3.3% failed compared with a 1.3% failure rate among 1417 patients who did not develop antibodies (p = 0.05). If deaths were counted as a failure, 3.8% of those who developed antibodies failed compared with 1.8% of those who did not develop antibodies (p = 0.05). Thus, there were significantly more failures in those who developed antibodies than in those who did not. This prospective study is ongoing to establish that the development of antibodies in patients with functioning grafts presages subsequent failure.

One might ask, ‘why did not 100% of those with antibodies fail?’ The answer is that we have only followed up these patients for a 6-month period. We are aware of only one study published to date in which the follow up of patients who have antibodies has been as long as 8 years. In the publication of Lee et al. (91) cited earlier and as shown in Figure 3, patients with well-functioning grafts may survive for long periods of time with antibodies … but they eventually fail. We hypothesize that antibody binds to the endothelium causing a cycle of injury and repair over many months and even years. The process of intimal vessel thickening is slow and gradual. It is critical to understand that all surveys of patients with functioning grafts show that approximately 30% of the patients already have antibodies (see section on ‘HLA antibodies are associated with chronic rejection’). This does not disprove the humoral theory, as the theory postulates that damage is gradual and all those with antibodies WILL eventually fail (Figure 3). Unfortunately, to date we are not aware of studies on the natural history of antibodies; for example, in some instances they may disappear as a result of immunosuppression and may then return. Hopefully our prospective study mentioned earlier will gather information on this issue.

Antibody specificity

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

Until now we have referred to antibody as detected by a panel of cells or antigens. Many studies have not had available cells from the original donor. With the recent development of flow cytometry beads having single antigens prepared from recombinant cells (92), it has become possible to study the specificities present in sera. Interestingly, patients who rejected a kidney transplant had antibodies against specificities other than those to which they were immunized. This phenomenon has actually often been encountered in the past. For example, Ceppellini carefully chose donors and recipients for his planned immunization program in order to obtain monospecific typing sera. However, despite great efforts, very few ‘clean’ sera with specificity directly against the donor mismatch were produced. In addition, screening thousands of pregnancy sera was necessary to find sera that were monospecific in their reactivity. For reasons still unknown, extra specificities are often produced upon immunization.

Lee et al. (91) also found that often patients who are rejecting their grafts do not have antibodies directed specifically against their donor. As such antibodies were found in sera AFTER rejection (92), we assume that DURING rejection the antibodies directed against the donor are absorbed by the graft and only the extra antibodies circulate in the peripheral blood. Thus, the strong association of antibodies with rejection in the studies of Lee et al. (91) resulted from detection of nondonor specific antibodies.

The nonspecific nature of the response could be explained by the idea that antibodies are merely indicators of immune responsiveness, and that they might not be directly involved in the rejection, as would be postulated by the humoral theory. After rejection of grafts, donor-specific antibodies were found (92), making it unlikely that the antibody is simply an indicator of responsiveness.

Consequences of accepting the humoral theory

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

An important consequence of adopting the humoral theory is that we can now treat patients by reducing antibody levels and monitoring antibodies. Three patients with acute humoral rejections following live donor transplants were treated successfully by plasmapheresis and IV IgG (93). Pre-emptive plasmapheresis and IV IgG treatment of five patients with a positive flow cytometry crossmatch was also successful. Immuno-absorption of antibodies with protein A columns was effective in five of six patients with a mean PRA of 65% for a mean follow up of 54 months (94).

Intravenous IgG treatment has been shown to reduce HLA antibody levels (95,96). Desensitization of patients with antibodies was effective in 13 of 15 patients treated with IV IgG (97). Although the exact mechanisms by which this occurs remains unclear (98), it assumes that antibodies are the principal agents of damage.

Treatment with tacrolimus and mycophenolate mofetil was effective in four instances of chronic humoral rejection in patients 4–16 years post-transplantation (99). After treatment, the titers of donor-specific antibodies dropped dramatically and the serum creatinines stabilized. MMF was also effective in reducing titers of anti-A and -B red cell antibodies in patients who had received ABO incompatible kidneys (100). Whether or not certain drugs influence humoral immunity can be investigated. In a study of 86 cardiac transplant patients, MMF treatment resulted in less antibody formation than with azathioprine treatment (101).

Treatment of acute cardiac humoral rejection with anti-CD20 monoclonal antibodies directed against B cells was effective in one patient whose rejection was reversed and who remained rejection free for at least 1 year (102).

Remaining issues

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

HLA antibody isotypes

The relative importance of Class I and Class II antibodies remains to be resolved (103). As for the antibody isotype, most of the tests were performed with IgG antibodies. In five patients transplanted across an IgM-positive crossmatch, hyperacute rejection was not found and the patients had good early function (104). Patients who had IgM-positive crossmatch by flow cytometry had slightly higher graft survival rates than those who were negative (105). IgA antibodies pretransplant were associated with higher graft survival (106–108).

Non-HLA antibodies

Antibodies that affect grafts may be against antigens other than HLA antigens. MICA antibodies, found in the sera of patients who rejected kidneys, are of particular interest because they are detected on endothelial cells but not lymphocytes (109–112). Antibodies were found against epithelia, monocyte, and endothelial lines in patients rejecting allografts (113–116). Also, antibodies to endothelial cells may not necessarily be polymorphic, but rather antibodies that occur secondarily to damage (117). Hyperacute rejection as a result of antibodies to endothelial cells has been reported (118).

Some antibodies may be helpful to the graft such as autoantibodies (119). When present before transplantation, antibodies against Fab have been shown to be beneficial (120), and more recently IgA anti-Fab autoantibodies have been shown to improve graft survival (108). They could possibly counteract the activity of conventional cytotoxic antibodies. Anti-idiotypic antibodies to HLA may also be counter reactive (121–123).

A second histocompatibility locus

A second histocompatibility locus, other than HLA, is important in transplantation. HLA identical sibling donor grafts are slowly rejected and graft vs. host reactions occur in bone marrow transplants from HLA-identical siblings. Antibodies against these minor histocompatibility loci have not yet been found.

Soluble antigens

The presence of soluble HLA antigens in serum may complex with HLA antibodies in serum, interfering with measurement of HLA antibodies (68124). The presence of soluble antigens in liver transplant patients may inhibit antibody action (125).

Mechanism of action

Antibodies are thought to be the key triggering factor in the humoral theory, but how it produces its damage through a cascade of events remains to be clarified. Studies of the transducing activation signals in endothelial cells following adherence of HLA antibodies have been reported (126127).

Immunogenic epitopes

Perhaps the most interesting work still pending is the determination of immunogenic epitopes, or the actual epitopes against which the antibody response is made. These immunogenic epitopes should provide us with more accurate HLA donor/recipient organ matching than the currently utilized ‘antigens’.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References

I have reviewed accumulated evidence supporting the humoral theory of transplantation. The purpose of a theory is to stimulate research proving its validity. My own work since 1959 (128) has been fueled by this hypothesis. Although antibodies can kill cells within minutes in vitro, perhaps the crucial new understanding is that antibodies may take many months or years to produce the chronic vascular endothelial thickening that ultimately chokes off the graft. The presence of antibodies in well-functioning grafts appears at first sight to prove that they are not important. Only by a longer follow up period can the significance of the antibodies be appreciated (see section on ‘HLA antibodies precede kidney rejection’).

I hope this review will stimulate a parallel review of the cellular theory. For example, what evidence is there that direct action of cells causes hypercute or chronic rejection? If cells cause acute rejections, for what fraction do they account?

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. HLA antibodies instantly kill a kidney: hyperacute rejection
  5. State of preimmunization is detected by HLA antibodies
  6. HLA antibodies are associated with acute early rejection
  7. HLA antibodies are associated with chronic rejection
  8. HLA antibodies are present after almost all kidney failures
  9. HLA antibodies precede kidney rejection
  10. Antibody specificity
  11. Consequences of accepting the humoral theory
  12. Remaining issues
  13. Conclusion
  14. Acknowledgment
  15. References
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