F

Viral peptide Typical antigen recognition

B. Direct Recognition of Graft: Allo-class I MHC

Recipient's T cell

Allo-MHC TCR Class I

Recognition of graft antigen

Fig. 17.13. CD8+ allo-recognition versus viral peptide recognition. CD8+ T cells recognize antigen (viral peptide) presented by infected cells expressing self-class I MHC. CD8+ T cells recognize allo-class I MHC directly if allo-class I MHC mimics self-class I MHC plus antigen. Most donor cells are targeted because all nucleated cells express class I MHC.

importance than for CD4+ T cells. It has been documented both experimentally and clinically that vigorous graft rejection occurs in the total absence of CD8+ T cells, but in the presence of CD4+ T cells, presumably following the activation of the nonspecific mechanisms referred to earlier.

Role of B cells

Because B-cell activation generally requires CD4+ T-cell mediated immune responses, it is difficult to demonstrate a unique role for antibodies in graft destruction. The presence of PREFORMED antibodies will initiate complement mediated tissue destruction minutes to hours after transplantation in so-called hyperacute rejection. Preformed antibodies to allografts often exist in muciparous women and in individuals who have rejected a first organ graft.

In the case of xenografts (e.g., pig grafts into humans) preformed, natural, circulating human antibodies recognize (cross react) with antigens expressed by the porcine blood vessels present in the graft. The predominant xenoantibody reactivity is one directed against the a1,3 galactosyl linkage of porcine carbohydrate antigens. Human cells lack an a1,3 galactosyl transferase, and this antigenic epitope does not exist in humans, so no tolerance to it is established. Exposure of the immune system during development to this antigen (on endogenous flora of the intestinal tract) induces high levels of anti-a1,3 galactose antibodies in all humans. When these human antibodies bind to porcine antigens they form immune complexes on the blood vessel wall. Because human complement proteins are always in circulation, the classic complement pathway is activated, leading to complement activation on endothelial cells lining graft blood vessels, activation of the coagulation cascade, thrombosis and graft loss.

Tissue Differences in Clinical Transplantation

Successful clinical transplantation of the following tissues/organs has become quite routine.

Corneal transplants occur in immunologically privileged sites and survive without immunosuppressive drug, because the foreign antigens expressed by the graft are not "seen" by host cells (except under inflammatory conditions, where local tissue permeability changes).

Heart transplants are standard clinical treatment for end organ failure following a number of insults (cardiomyopathies, chronic congestive heart failure, ischemic damage); 88% of patients survive at least one year posttransplantation. One problem with heart transplants is the high incidence of atherosclerotic disease in the recipients (including within the donor heart) occurring in the years following successful transplantation. This represents either an effect of the drugs used to avoid rejection and/or the long-term immune effects of subclinical rejection episodes.

Liver transplants are resistant to rejection once any early acute rejection episodes pass, and long-term graft survival is similar for both well-matched and unmatched tissues, with 80% of patients surviving at least one year. Both clinical and experimental data suggest that the presence of an allogeneic liver graft facilitates survival of another organ graft from the same donor. One explanation offered for this phenomenon is that the liver induces long-term tolerance because it is itself a lymphohematopoietic organ and stem cells from the donor liver migrate and "seed" recipient lymphoid tissues, inducing functional chimerism. Understanding the immunology of this phenomenon holds hope for progress in transplantation in general.

Kidney transplant survival after one year is approximately 90%, even for cadaveric kidney grafts (slightly higher rates are seen for living related grafts). Given an endless supply of organs, this, rather than continuous dialysis, is the primary treatment for renal failure. Nevertheless patients continue to take immunosup-pressive drugs for the rest of their lives, producing, as it does for all transplant patients, significant side effects (drug toxicity; increased risk of infectious disease; increased incidence of malignancy). Since clinical kidney transplantation has been practiced over the longest period of time (30 years) changes in chronic survival of these grafts over this time can be measured. These data show unequivocally that while acute graft loss has slowed considerably (one year survival now approaches 90%, compared with less than 50% 20 years ago), the rate of chronic graft failure is relatively unchanged. These results highlight the urgent need for improved understanding of the (immuno)biology of chronic rejection.

Pancreas transplants are appealing for the treatment of diabetes and, combined with kidney grafts, for diabetic renal failure. Combined pancreas/kidney grafts survive well, with success rates comparable to that of kidneys alone. Isolated pancreas tissue may be given as a single cell suspension (islet grafts). Preliminary studies suggest these may survive optimally (and return the patients to normoglycemia) if given into the portal vein. The biological significance of the superior results following infusion into the liver bed remains unclear.

Bone transplants have been used to provide an inert "scaffold" for patients to bridge the time to replace allogeneic tissue with host bone matrix. Since bone grafts are avascular immune rejection is generally not a problem.

Bone marrow transplants are used to treat a variety of anemias, leukemias and lymphomas. Some problems are relatively unique to bone marrow transplantation. Rejection of allogeneic donor stem cells by immunocompetent hosts (host vs graft rejection) remains a problem, as in the case of solid organ grafts, which is treated using immunosuppressive drugs. The graft tissue is itself a source of lymphohematopoietic cells, capable of generating its own, donor-derived, immune system, which can recognize the host as foreign, resulting in the development of graft-versus-host-disease (GvHD). Other organ grafts where GvHD can also become a problem include the intestine and liver. This is easiest understood in terms of evidence that the liver represents an excellent adult source of hematopoietic stem cells, while intestinal transplantation also involves simultaneous transplantation of donor mesenteric lymphoid tissue and the Peyer's patch glands lining the intestinal wall.

Graft-Versus-Host Disease

In graft-versus-host disease (GvHD) donor T cells present in the graft initiate rejection of all host tissue. Donor CD8+ and/or CD4+ T cells are activated when they interact with host cells expressing class I and/or class II MHC. Recipients of bone marrow transplants are themselves immunologically compromised and unable to initiate a counter attack. Skin sloughing, diarrhea, inflammation of the lungs, liver and kidneys are common problems associated with this disease, reflecting the end result of chronic inflammatory attacks on these organs/tissues, with altered tissue permeability, cell and fluid migration (Chapter 10).

This crucial role of T cells implied that T-cell depletion of the donor graft would eliminate GvHD. In practice, however, while removal of all donor T cells diminished GvHD, it concomitantly decreased engraftment of the donor bone marrow. Cytokines, often donor-T-cell-derived, are required for bone marrow engraftment. Accordingly, general practice now is to deplete donor T cells from the marrow prior to transplantation and simultaneously infuse patients with cy-tokines (IL-3 and GM-CSF) believed to "speed up" restoration of the lymphohematopoietic system from donor stem cells. Other sources of stem cells besides bone marrow are also under investigation, including cytokine-expanded CD34+ peripheral blood stem cells, and cord blood CD34+ cells. Banking of stem cells (rather like blood banking) has been initiated to provide an HLA-typed source of material for patients in urgent need.

Bone marrow transplantation is often the treatment of choice for leukemia/ lymphoma. In such cases an added benefit of the presence of residual donor T cells in the bone marrow inoculum was a killing effect these cells had directed at residual host cancer cells, a so-called graft vs leukemia effect (GvL). When clinicians were most aggressive in eliminating T cells to avoid GvHD, the beneficial effect of GvL was also lost. Understanding the nature of the cells involved in GvHD and GvL is important, because if they do recognize distinct antigenic determinants there is hope that we may eventually be able to eliminate GvHD but preserve a GvL effect.

Immunosuppression in Transplantation

Nonspecific immunosuppression

The immunosuppression required for effective long-term survival of any given graft differs between individuals. Nevertheless, high doses of immunosuppressive drugs generally lead to significant adverse effects, including an increased susceptibility to infectious disease, development of lymphoid/skin malignancies, and toxicity from the drugs themselves. These drugs are used clinically: Cyclosporin A (CsA); prednisone; azathioprine; FK506; rapamycin; and anti-CD3 and anti-CD4 antibodies.

Cyclosporin A and FK506 block the transcription and production of IL-2 by CD4+Th1 cells. They bind calcineurin in the cytoplasm and interfere with delivery of the IL-2 gene-activating stimulus to the nucleus.

Rapamycin inhibits a later stage in IL-2 gene transcription and synergizes, in immunosuppression, with FK506 or CsA.

Prednisone is a nonspecific anti-inflammatory agent, suppressing activation of macrophages and release of IFNy. Rejection is inhibited at the antigen processing/presentation stage.

Azathioprine, an antimetabolite, is an analog of 6-mercatopurine. It inhibits purine metabolism and blocks cell division (and clonal expansion of activated cells).

Anti-CD3 antibodies suppress the activity of all T cells. Interaction of T-cell surface CD3 with anti-CD3 can cause an early, transient, activation of T cells before down regulation of CD3 expression occurs. Anti-CD3 is a murine antibody, and patients frequently generate an immune response to it, making further treatments less effective.

Anti-CD4 antibody treatment is coming into clinical practice to treat graft rejection, following many years of successful experimental trials.

Specific immunosuppression (tolerance)

This remains an unrealized goal for human transplantation. One of the seminal early observations in clinical transplantation was that prior exposure to donor antigens surprisingly led to prolonged survival of grafted organs, particularly in renal graft recipients pre-exposed to antigen in the form of blood transfusions. Transplantation was initially avoided in these individuals because of the fear of increased rejection (immunological memory). However, clinical experience showed grafts in these patients often fared better, not worse, than grafts to nontransfused individuals. These data form the basis of one of the few protocols currently used to produce donor-specific tolerance, the pretransplant (or peritransplant) transfusion protocols. Here the recipient receives deliberate infusions of donor cells (blood and/or bone marrow), in addition to the organ allograft.

Many hypotheses were used to explain the increased survival following transfusion. One suggests that pretransplant transfusion actually activates cells involved in allorejection, and that the immunosuppressive drugs given with the allograft eliminate these clonally activated T cells, producing operational tolerance of the graft. Alternatively, pretransplant transfusion may induce specific (or even nonspecific) "suppressor cells" capable of inhibiting graft rejection processes. Yet another model suggests that following transfusion preferential activation of CD4+ Th2 cells occurs, producing IL-10 (or IL-13) which suppresses the activation of CD4+ Thl cells that secrete IL-2 and IFNy, both of which are increased during rejection episodes. This notion that graft rejection is correlated with CD4+Th1 activation, and graft survival with CD4+Th2 activation, remains highly controversial.

Debate continues concerning the role of and/or need for persistent donor hematopoietic chimerism in graft recipients to produce long-term graft survival. Data from several groups suggests tolerance occurs to organ allografts only in cases where donor-derived dendritic cells migrate out from the donor organ, re-populate lymphoid tissues of the host, and persist. If tolerance is a passive process, dependent merely upon persistent donor antigen per se, it should occur simply from persistent presentation of allo-MHC itself on the grafted tissue. However, if tolerance is an active process, associated with, e.g., recipient CD4+Th2 activation, one might expect that persisting donor bone marrow-derived antigen presenting cells might be needed for tolerance maintenance. This proposal underlies some of the newer trials incorporating the introduction of small numbers of donor bone marrow cells to recipients of solid organs. This has also been used to explain why the liver, a known source of hematopoietic cells, might be so adept at promoting not only its own survival, but that of other (cotransplanted) organs.

Summary

In transplantation cells/tissue from one individual (a donor) are given to a second individual (a recipient). Transplants are classified according to the genetic disparity between donor and recipient (isografts: no genetic difference; allografts, transplants within a species; xenografts, transplants across a species barrier), and by the degree of immunological rejection they provoke. The latter is divided by time and the immunological mechanisms involved into hyperacute rejection (minutes to hours; antibody and complement mediated); acute rejection (weeks to months; T-cell mediated); and chronic rejection (months to years; mechanism(s) unclear).

The genetic disparity between donor and recipient helps predict the outcome of allografts, because genes of the major histocompatibility complex (MHC) encode the molecules that induce the most vigorous rejection episodes. "Tissue-typing" pretransplantation is an attempt to minimize MHC disparity between donor and recipient, using serological, mixed lymphocyte typing reactions, and (newer) molecular typing techniques. It is becoming increasingly clear that donor/recipient disparity at other genes, encoding so-called minor histocompatibility antigens (MiHs), sometimes produce as profound a rejection episode as differences at MHC loci.

Rejection is generally a function of the T-cell arm of the immune response, though bystander cells, especially macrophages, are often recruited following release of mediators (cytokines, etc.) from activated CD4+ T cells. CD4+ T cells assist the differentiation of other cytolytic effector CD8+ T cells, which lyse graft cells directly. A high frequency of T cells can recognize foreign MHC molecules, far greater than that number recognizing so-called nominal antigen. The manner in which these T cells "see" allo-MHC, whether DIRECTLY (without processing of MHC molecules as antigen, and presentation on antigen presenting cells) or INDIRECTLY (following such processing) dictates the nature, number and type of T cells activated, and often the severity of rejection. In unique circumstances (preimmunized recipients or recipients of grafts across a species barrier, xenotransplantation) antibody responses are important.

Following transplantation recipients receive long term nonspecific immunosuppressive drugs to prevent rejection. These treatments often cause significant side effects, including drug-related toxicity and an increased susceptibility to infection and malignancy. Protocols that induce graft-specific tolerance without the need for long-term nonspecific immunosuppression would be ideal. One uses donor specific pretransplant transfusion, though the mechanism(s) by which tolerance induction is achieved remain unclear.

Development of chimerism (coexistence of donor and host hematopoietic cells in the same host) may be essential for long-term tolerance, and probably occurs frequently after bone marrow transplantation. In this case the early period following transplantation is often also associated with a reaction of donor immune cells against the host (a graft-versus-host reaction), rather than the normal host anti-graft reaction. When bone marrow transplantation is used in treatment of malignancy (leukemia/lymphoma), an anti-host reaction can be beneficial, a so-called graft-versus-leukemia effect. Balancing the outcome of all of these reactions is a major problem following bone marrow transplantation.

Clinical Cases and Discussion

Clinical Case #33

Gary is a 21-year-old boy with severe Crohn's disease. Multiple previous surgeries have resulted in home IV feeding for 6 months. He asked to be a candidate for an intestinal transplant program at the University Hospital and received a small intestinal transplant 4 weeks ago. He is given standard immunosuppressive treatment including cyclosporin A and FK506. He has gained weight, but has a diffuse "weeping" rash over his body, abdominal cramps and a fever for 5 days.

Questions and Discussion: Case # 33

1. Six key features we need to bear in mind in discussing this case are:

Young male

Immunosuppressive therapy One month post intestinal transplant Diffuse "weeping" rash Fever of 5 days duration Abdominal cramps

2. An early complication of transplantation is acute graft rejection. The time frame of 4 weeks is right for acute rejection. How does this occur?

The degree of MHC incompatibility between donor and host is critical. MHC antigens are products of HLA-A, -B, and -C loci (class I MHC), and HLA-DP, -DQ, -DR loci (class II MHC). MHC differences between the donor and recipient are minimized by pretransplant "matching" of donor/ recipient.

3. The initial step in acute rejection is the recognition of the allogeneic graft as foreign by host CD4+ and CD8+ T cells. How do these cells recognize foreign MHC?

Approximately 1%-2% of the total T-cell population is reactive with any one allo-MHC antigen, whereas only 1 in 10,000 to 1 in 1,000,000 T cells of the total T-cell population is reactive to a nominal protein antigen. One explanation suggests that allo-MHC (with or without peptide) mimics self-MHC plus (unspecified) antigen. CD4+ T cells recognize allo class II MHC, while CD8+ T cells recognize allo class I MHC.

4. Explain the role of each class of T cells in allogeneic graft rejection. Activated host CD4+T cells release Type 1 cytokines which contribute to nonspecific inflammatory processes (e.g., IFNy/TNF) and IL-2 which is a growth factor for T cells expressing IL-2 receptors. IL-2 is also required for differentiation of naive CD8+ T cells to mature CTL, causing direct cytotoxicity to graft cells.

5. Acute rejection causes nonspecific symptoms (e.g., the fever here) as well as physiological "failure" of the graft(leading, in kidney grafts, to rising serum creatinine; in intestinal grafts, to weight loss, cramping etc.). What is an immunological basis for cramping and fever?

Cramping could be caused by nonspecific mediators induced by cytokines produced by activated CD4 cells (e.g., activation of mast cells to release histamine). Activated CD4+ T cells secrete Type 1 cytokines (including IFNy and TNF) that further activate macrophages to secrete IL-1. IL-1 can act on the hypothalamus to induce fever.

6. Acute rejection episodes are treated by increasing nonspecific immunosuppression. The side-effects of immunosuppression often cause significant problems. What are some of these?

Increased infection, drug toxicity and increased evidence of malignancy.

7. The incidence of malignancy is relatively restricted to two types. What are they?

Lymphomas and skin malignancies.

8. Infection could cause this fever, particularly since he is on immunosuppres-sive therapy. What infections are prominent early after transplantation? Viral infections (serum Ig levels do not fall, but functional T-cell activity is compromised!). Cytomegalovirus (CMV) infections are particularly prominent.

9. What drug toxicity complicates immunosuppressive therapy? Hypersensitivity reactions are possibilities, but are rare because the drugs themselves are immunosuppressive. Organ toxicity is common, e.g., renal toxicity and neurotoxicity are common with cyclosporin A and FK506.

10. Gary has some (not all) of these findings (fever, intestinal cramping, loss of weight). What remains unexplained, and what is a possible cause?

The rash remains unexplained. Elevated permeability of blood vessels following cytokine release by CD4+ T cells would account for the "weeping rash", the cramps, and fever.

11.In intestinal transplantation DONOR lymphoid tissue is transplanted as part of the intestinal graft. The intestine is a source of some 50% of the total body lymphoid pool. What is a problem in this type of transplantation? Graft-vs-host disease (GvHD) is a significant problem.

12. Would GvHD present with cramping, fever, rash, and intestinal cramps? In GvHD massive cytokine production (from both activated host and donor CD4 cells) occurs, a so-called cytokine storm. This accounts for the "weeping rash" (elevated permeability of vessels following cytokine release) and the cramps (and fever).

13. What are treatment options?

i Increased (or different) immunosuppression, but beware of infection and/or malignancy.

ii Graft removal. You must weigh the pros/cons of different treatments.

14.How could graft failure be measured directly?

We need some specific assay for intestinal function (like serum creatinine for the kidney). The kidney normally filters creatinine from the blood, and failure to do so, producing rising serum creatinine, is a useful surrogate marker for declining kidney function from all causes. Measuring the absorptive function of the intestine is a good approach here.

Clinical Case #34

Adriana is 4 years postcardiac transplantation for cardiomyopathy that developed after receiving chemotherapy (adriamycin) for breast cancer. Routine annual endomyocardial biopsies, the last 6 months ago, were read as normal, with no signs of rejection. There has been no change in her antirejection therapy for the last 2 years; she is on prednisone and cyclosporin A. Her son found her at home quite confused and with a droop on the left side of her face/mouth. Routine blood work, including measurement of cardiac muscle enzymes, physical exam, and electrocardiogram (to check the heart) is normal. How do you proceed?

Questions and Discussion: Case #34

1. List the six likely key features we need to bear in mind in discussing this case.

Mature female Heart graft

Stable on anti-rejection therapy

Blood work is normal, including cardiac muscle enzymes Cardiogram is normal Physical exam is normal

2. Is this a case of hyperacute or acute rejection? How do these differ immunologically and in treatment?

Hyperacute rejection occurs in the immediate aftermath of transplantation and is antibody and complement mediated. It requires immediate graft removal. Acute rejection occurs weeks to months after transplantation, involves (T) cell mediated organ damage and is treated by increasing immunosuppressive treatment.

3. In addition to the time, what other evidence makes acute rejection unlikely? Acute rejection involves organ damage, following CD4 and/or CD8 mediated "attack". Think of organ-specific "markers" for the damage. For the heart, the EKG (cardiogram), and measurement of specific cardiac muscle enzymes would assess killing (lysis) of heart cells, with release into the serum of cardiac muscle enzymes. This patient has a normal cardiogram and normal cardiac muscle enzymes. [In kidney grafts, you would measure creatinine.]

4. Could this be a case of chronic rejection? How would this manifest?

Chronic rejection correlates with release of nonspecific growth factor-like mediators (e.g., fibroblast growth factor, endothelial growth factor etc.) and is an insidious fibrosing/proliferative reaction, relatively refractory to immunosuppressive treatment. A fibrotic heart is a poor pump, resulting in poor oxygenation of tissues. This might cause generalized neurological deficits (e.g., Adriana's confusion).

5. In the absence of acute, hyperacute, or chronic rejection, what about the side effects of the treatment she received for her transplant. Immunosup-pressed individuals are susceptible to?

a. Malignancy (lymphomas and skin cancer)

b. Infection (especially viral); antibody levels are generally unaffected.

c. Toxicity directly and indirectly from the drugs themselves.

6. How could a malignancy, lymphoma or skin cancer, manifest as confusion? How would you investigate?

Immunosuppression impairs tumor surveillance, so a secondary metastasis (to the brain) from her original breast cancer would be a concern in this lady, as would a new central nervous system lymphoma (Chapter 16). You should order a CT scan.

7. Assume that the tests/examination from #6 are normal, is there evidence for infection? What viral infections are seen in immunosuppressed transplant patients? How would you detect them?

Nothing suggests infection here, and even her blood work is normal. Two viral infections common in immunosuppressed transplant patients can present this way, cytomegalovirus (CMV) and herpes simplex virus (HSV). Serological titers of the virus might be measured (look for IgM (a new response) in a person known to be seronegative before transplantation; or elevated IgG, if previously positive). Alternatively, monitor a "response to treatment" or biopsy tissue.

8. Assumingall tests are negative we are left with drug toxicity. What are toxic side effects of cyclosporin A and prednisone?

Cyclosporin A is nephrotoxic (damages the kidney) and neurotoxic (damaging nervous tissue). Neurotoxicity is more evident in peripheral nerves (peripheral neuropathy) than in the central nervous system. Prednisone increases atherosclerotic disease, both in grafted organs (here the heart) and elsewhere (e.g., the brain). Narrowing of blood vessels puts people at risk for increased clots (emboli) to the heart (a heart attack) and the brain (a stroke). The latter is the most likely problem for this unfortunate lady.

Test Yourself

Multiple Choice Questions

1. A patient on your transplant service is enrolled in a study designed to investigate levels of cytokines produced during various stages of transplantation/acceptance/rejection. A patient showing elevated levels of IL-2 in the grafted organ would likely be undergoing:

a. "A healing in" process associated with a graft acceptance b. Graft rejection c. Cytotoxic reaction to immunosuppressive drugs d. Infection e. None of the above

2. XL received a kidney graft from her sister 6 years ago but lost the graft to rejection. This morning she underwent a further transplant from a younger brother. Ninety minutes following surgery she suffers severe cramps in the abdomen, is febrile, and looks quite unwell. She might be suffering from:

a. Chronic rejection b. Acute graft rejection c. Cytotoxic T-cell mediated graft damage d. Hyperacute graft rejection e. Surgical sepsis

3. Appropriate treatment for the patient in question 2 would be:

a. Anti-T cell antibodies b. Immunosuppression c. Removal of the graft d. Analgesia e. Anti-pyretics (anti-fever drugs)

4. You are running a tissue-typing laboratory and are faced with matching a potential kidney transplant recipient with one of several unrelated donors. Serology indicates 5/6 MHC matches. Which of the following would be the MOST judicious course of action?

a. Proceed with transplantation, with no immunosuppression b. Proceed with transplantation, using cyclosporin and prednisone c. Await further matching data from PCR (6 hours)

d. Await further matching from MLR (72 hours)

5. A child receives a bone marrow transplant from an HLA identical sibling. After successful engraftment, 3 weeks later the child has diarrhea and a rash on the palms and soles of the feet, spreading to the trunk, with jaundice. Administration of an anti-T cell serum plus cyclosporine produces improvement. The most likely cause is?

a. Inadequate numbers of donor cells were transfused b. Donor lymphocytes are reacting with antigens on the recipient's cells c. Present symptoms are the long term effects of original drug ingestion d. There is a superimposed viral infection (CMV)

e. There has been a failure of the graft to take

Short Answer Questions

1. Distinguish between autograft, isograft, allograft and xenograft.

2. Name three pieces of evidence for immune rejection of allografts.

3. What are the various potential phases of graft rejection and how does one treat them clinically?

4. What chromosomal locus (i) codes for the major gene(s) involved in human graft rejection and how do we routinely test for human histocompatibility antigens?

5. What unique problems surround the use of bone marrow transplants?

Acquired immunodeficiency syndrome (AIDS) 222 Active immunization 241, 258 Acute rejection 106, 373, 391 Adaptive immunity 2 Addressin 134

Adhesion molecules 34, 134, 169 Adjuvants 3, 24, 244, 258, 282 Affinity 71

Affinity maturation 157 Allelic exclusion 132 Alloantigens 107 Allografts 368, 391 Allotransplant 107 Allotypes 69, 70 Alphafetoprotein (AFP) 342 Alternative pathway 20, 32 Alternative pathway C5 convertase

(C3bBbC3b) 89 Anaphylatoxins 32, 93, 194 Anergy 169

Ankylosing spondylitis 295 Anti-CD4 antibody treatment 390 Anti-idiotypic antibodies 72 Antibody 3, 11, 20, 69 Antibody-mediated cellular cytotoxic-

ity (ADCC) 45 Antigen 22

Antigen presenting cells (APC) 10, 51, 169

Antigen-dependent B-cell differentiation 12, 153 Antigenic determinant 22 Apo-1 184 Apoptosis 134, 182 Aspergillus 227 Autografts 368 Autoimmunity 290 Azathioprine 390

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