AUTHOR AND EDITOR INFORMATION

Section 1 of 6  

• Authors and Editors
• Introduction
• Historical Background
• Mechanisms for Self-Tolerance
• Induction of Tolerance in Transplant Patients
• References

INTRODUCTION

Section 2 of 6  

• Authors and Editors
• Introduction
• Historical Background
• Mechanisms for Self-Tolerance
• Induction of Tolerance in Transplant Patients
• References

Immunologic tolerance is a state of immune unresponsiveness specific to a particular antigen or set of antigens induced by previous exposure to that antigen or set.

Induction of immunologic tolerance has been achieved and studied in numerous laboratory animal models, but it remains an elusive goal in clinical organ transplantation and in the management of autoimmune disease in humans.

Transplant tolerance is defined as a state of donor-specific unresponsiveness without a need for ongoing pharmacologic immunosuppression. Transplantation tolerance could eliminate many of the adverse events associated with immunosuppressive agents. A strategy to develop tolerance would also be of value in autoimmune diseases, such as juvenile-onset diabetes mellitus and rheumatoid arthritis.

Safe, reliable strategies for the induction of full tolerance have not yet been developed. However, the induction of partial tolerance, in which lower-than-conventional amounts of ongoing pharmacologic immunosuppression are needed, has been demonstrated with several regimens.

HISTORICAL BACKGROUND

Section 3 of 6  

• Authors and Editors
• Introduction
• Historical Background
• Mechanisms for Self-Tolerance
• Induction of Tolerance in Transplant Patients
• References

The phenomenon of tolerance was observed in 1945, when Ray Owen, who had a special interest in bovine blood groups, discovered that most dizygotic-twin cattle fetuses had placental anastomoses with each other and that they shared their blood supply in utero. These cattle maintained a stable mixture of each others' red cells throughout their lives. He noted that, despite their having distinctly different blood groups, transfusions between the twins did not cause any transfusion reaction, which occurs between nontwin cattle of different blood groups. This mosaicism is an example of immune tolerance.

In 1947, Rupert Billingham and Peter Medawar were studying the use of skin allografts in young cattle to distinguish identical and fraternal twins. This work was done to identify the sterile female twin of a male calf (ie, freemartin), a point of agricultural importance because the freemartin female bovine was totally useless to breeders and dairy farmers. The skin grafts were essentially accepted regardless of whether the cattle were identical or fraternal. However, skin grafts exchanged between unrelated cattle were always rejected. The study did not help in distinguishing the 2 kinds of twins.

In 1949, Billingham and Medawar came across Owen's work in a monograph by Frank Macfarlane Burnet and Frank Fenner entitled "The Function of Antibodies." This publication helped them make sense of their work. The authors postulated that the age of the animal at the time of its first encounter with a foreign body was the critical factor in determining its responsiveness and, hence, its recognition of nonself-antigens.

Billingham, Medawar, and Leslie Brent, Medawar's postgraduate student, now envisioned the possibility of having adult animals accept tissue allografts by reproducing in the laboratory what occurred naturally in cattle. They aimed to prove that tolerance could be artificially induced. If living cells from mouse strain CBA were injected into an adult mouse of strain A, some immunologic process destroyed the CBA cells, and the A-line mouse that received the CBA cells quickly destroyed any subsequent graft from the same donor strain. However, if the CBA cells were injected into an A-line fetus or newborn who was still immunologically immature, the CBA cells were accepted, and any future grafts from the strain A donor were accepted.

In 1960, Burnet and Medawar shared the Nobel Prize in Physiology or Medicine for their work in acquired immunologic tolerance to tissue grafts.

MECHANISMS FOR SELF-TOLERANCE

Section 4 of 6  

• Authors and Editors
• Introduction
• Historical Background
• Mechanisms for Self-Tolerance
• Induction of Tolerance in Transplant Patients
• References

Self-tolerance is a learning experience for T cells. Tolerance can occur at 2 levels: central and peripheral.

Central and/or intrathymic tolerance

The chief mechanism of T-cell tolerance is the deletion of autoreactive T cells in the thymus. Immature T cells migrate from the bone marrow to the thymus, where they encounter peptides derived from endogenous proteins bound to major histocompatibility complex (MHC) molecules on thymic epithelial cells.

Double-positive (CD4⁺ and CD8⁺) thymocytes initially undergo random generation of different T-cell receptors (TCRs). Positive selection, also called thymic education, ensures that only clones with TCRs and moderate affinity for self-MHC are allowed to develop. Negative selection by means of apoptosis (programmed cell death) occurs when T cells do not produce functional TCRs, when TCR rearrangement fails, when T cells have low affinity for the MHC–self-peptide complex, or when T cells have extremely high affinity for such complexes. Negative selection also results in the deletion of some thymocytes that have TCRs and reactivity and some thymocytes that interact with autoantigens presented by interdigitating cells and macrophages at the corticomedullary junction. The remaining cells lose either CD4 or CD8 and leave the thymus to function in the periphery as mature, functional CD4⁺ or CD8⁺ T cells.

Peripheral tolerance

Many potentially autoreactive T cells escape intrathymic deletion, reflecting the fact that many antigens are absent intrathymically or present at insufficient levels to induce tolerance in the thymus. Several peripheral (nonthymic) mechanisms prevent autoimmunity.

Sequestration of antigens into privileged sites

Some antigens are sequestered into privileged sites away from the immune system because of physical barriers, such as tight junctions, or immunologic barriers, such as expression of Fas ligand (FasL) or little expression of MHC class I. Antigen-presenting cells (APCs), and subsequently T lymphocytes, may never encounter these self-antigens. Therefore, they remain ignorant of these antigens. At some of these sites, proinflammatory lymphocytes are controlled by apoptosis due to the expression of FasL or the secretion of cytokines such as transforming growth factor-beta (TGF-beta) or interleukin (IL)-10.

When T cells enter these sites, their Fas interacts with the FasL of these sites, and they undergo apoptosis. Privileged sites include the brain, the testis, and the anterior chamber of the eye. Transplanted tissues are most likely to survive in these privileged sites because of the tight control of proinflammatory lymphocytes.

Apoptosis of T cells due to persistent activation or neglect

Apoptosis of lymphocytes is an important mechanism of immune control and homeostasis. Apoptosis contributes to the deletion of clones that are persistently activated and of activated lymphocytes when the immune response is no longer needed (eg, after an infection clears). Cells that are persistently stimulated undergo activation-induced cell death involving Fas-FasL signaling or tumor necrosis factor. Most T cells that remain after antigens are no longer present are deprived of the stimuli to survive and undergo passive cell death.

Clonal anergy

T lymphocytes require 2 signals to become activated, to proliferate, and to differentiate. The first is the recognition of an appropriate MHC-peptide complex by the TCR. The second signal is delivered by costimulatory molecules also expressed by APCs. Lack of costimulation causes anergy, that is, T cells fail to respond to the MHC-peptide complex and remain unresponsive to subsequent challenges, even with costimulation.

CD28 is the main costimulatory ligand expressed by naïve T cells encountering an antigen. Signaling by means of CD28 enhances T-cell proliferation by boosting IL-2 production by T cells, which promotes activation and proliferation. It also enhances expression of CD40 ligand, which interacts with CD40 on APCs and which induces upregulation of costimulatory molecules CD80 (B7-1) and CD86 (B7-2) to enhance costimulatory signaling to responding T cells.

T lymphocytes also express CD152 (CTLA-4) after CD28 binds to its ligands B7-1 and B7-2 on APCs. The interaction of CTLA-4 and B7 molecules decreases opportunities for B7-CD28 binding and downregulates T-cell activities, such as production of IL-2, to reduce T-cell proliferation. CD28 interacts with B7 molecules, first leading to T-cell activation. However, after this effect peaks, upregulation of CTLA-4 with its relatively high affinity for B7 molecules limits the degree of activation.

In the last 15 years, much interest has focused on the development of agents that contain CTLA-4 or that are structurally similar to CTLA-4, as costimulation blockade in the laboratory not only prolongs the time to rejection in a number of allograft models but also induces tolerance in combination with other agents in several animal models.

Regulatory T cells

Regulatory T cells (Tregs), also called suppressor T cells, suppress the activation of clone-specific T-cell activity. Tregs account for 10-15% of CD4⁺ T cells and express a transmembrane protein called CD25, an alpha chain of the receptor for IL-2. These CD4⁺CD25⁺ Tregs are anergic to TCR-mediated activation but potently suppress the activation of other T cells. Not all CD25⁺ cells are regulators. Some naïve T cells upregulate CD25 in response to antigen, a change that represents an active rather than suppressive immune response. It is now clear that the thymus produces anergic but suppressive CD4⁺25⁺ T cells (which are also identified by the expression of FoxP3, the transcription factor responsible for their development). These T cells suppress activation and expansion of autoreactive CD4⁺25^- populations.

Studies in mice have shown that Tregs are antigen specific and that they regulate peripheral tolerance by producing suppressive cytokines, such as IL-10 and TGF-beta. They depend on continuous antigen exposure to stay active. Removal of the antigen reduces the quantity of cells.

In allograft rejection, direct stimulation of T cells in response to donor antigen presented by donor APCs had been the focus of transplantation for many years. However, indirect antigen presentation, in which self-APCs present donor peptide in an MHC-restricted fashion, is responsible for the induction of antigen-specific Tregs that can directly and indirectly suppress other alloreactive T cells. Positive costimulation with CD28 appears to be necessary for the development of intrathymically derived Tregs, but costimulation blockade with CTLA-4 is needed for peripherally acquired suppressor Tregs to develop.

Tregs are also responsible for maintaining tolerance by broadening suppression by what is termed linked-suppression to additional antigens expressed in the tolerated tissue and to further cohorts of naïve T-cells as they develop. Immunologist Herman Waldmann described this phenomenon as a process of infectious tolerance. Tregs from tolerant animals can be transferred to naïve animals, in which they subsequently confer antigen specific tolerance, including tolerance to skin and organ allografts. Tolerance induction by expanding and transferring donor Treg to an allograft recipient or by means of the ex vivo development of Treg from recipient T cells are intriguing but yet-untested strategies in humans.

Oral tolerance

Oral administration of protein antigen is used to induce specific immunologic unresponsiveness and may be a potential future therapy for some autoimmune disorders. The specific mechanisms of how oral antigen induces tolerance are still unclear.

Studies have demonstrated that feeding antigen in high dosages results in the deletion of reactive T cells, but it does not promote the generation of Tregs. Small doses of antigen, administered orally or intranasally, induce antigen-specific antibodies, increase the inhibitory cytokines IL-4 and IL-10, and induce Tregs in gut-associated lymphoid tissue (GALT).

IL-4 is a factor involved in the differentiation of TGF-beta–secreting T cells from naïve splenic T cells, also known as T helper 3 (Th3) cells. Th3 cells have suppressive properties for T helper 1 (Th1) and T helper 2 (Th2) cells.

A phenomenon known as bystander suppression is observed with oral tolerance because oral antigen–induced Tregs also secrete antigen-nonspecific cytokines after fed antigen triggers them. Nonspecific cytokines can suppress inflammation in the microenvironment where the fed antigen is localized. Therefore, knowledge of the specific antigen being targeted might not be needed as long as the fed antigen can induce Tregs to get to the target and suppress inflammation. Oral administration of antigen suppressed or reversed autoimmune disorders in several animal models; thus, they can induce self-tolerance. However, to date, attempts at oral tolerance have not been successful in any human autoimmune diseases, including rheumatoid arthritis, diabetes, and multiple sclerosis.

ABO compatibility

ABO blood-group antigens, present on many tissues and RBCs, are other major antigens encountered during transplantation. ABO compatibility depends on the presence or absence of specific antibodies in the recipient's serum against specific antigens on donor RBCs. Adults typically have preformed antibodies to donor blood-group antigen. Therefore, transplantation of solid organs from ABO-incompatible donors is contraindicated because of the risk of hyperacute rejection mediated by the preformed antibodies to the donor RBCs. This contraindication does not apply to newborns and infants because their ABO isohemagglutinins are not yet formed or well developed.

Cardiologist Lori West and colleagues examined 10 infants and children aged 4 hours to 14 months who received ABO-incompatible heart transplants between 1996 and 2000.¹ Plasma exchange was done during cardiopulmonary bypass to remove antibodies, and immunosuppression therapy was given afterward. Rejection was monitored by means of endomyocardial biopsy. Follow-up ranged from 11 months to 4.6 years. The researchers reported an 80% survival rate with 2 early deaths that were not attributed to ABO incompatibility. No morbidity was attributed to ABO incompatibility. This observation mimics findings from animal models of neonatal tolerance in which immunologically immature recipients could accept incompatible grafts and develop tolerance.

ABO-incompatible heart transplantation during infancy results in the development of B-cell tolerance to donor blood-group A and B antigens. This tolerance occurs by eliminating donor-reactive B lymphocytes, which may depend on persistence to some degree of antigen expression.

In adults, transplantation of ABO-incompatible livers has been performed in emergency situations with reasonable success, though reported cases have not involved tolerance. Transplantation of ABO-incompatible organs in adults by using the antibody-depleting strategies of plasmapheresis, splenectomy or use of anti-CD20 antibody, and intensive immunosuppression has been successfully undertaken in a few centers. Of interest, long-term plasmapheresis is not necessary, and ongoing graft function with immunosuppression can be achieved despite the return of antibodies against donor blood groups.

INDUCTION OF TOLERANCE IN TRANSPLANT PATIENTS

Section 5 of 6  

• Authors and Editors
• Introduction
• Historical Background
• Mechanisms for Self-Tolerance
• Induction of Tolerance in Transplant Patients
• References

Clinical research has been conducted to induce full or partial tolerance in transplant patients. These strategies cannot be recommended for general clinical use until further evidence-based studies are available.

Tolerance can be induced by using allogenic hematologic stem cells or marrow cells to inoculate immune naïve hosts, such as neonates, or adults who have undergone myeloablative regimens (eg, total-body irradiation).

Full tolerance

The holy grail of organ transplantation is full immunologic tolerance, a state of indefinite survival of a well-functioning allograft without a requirement for maintenance immunosuppression. In addition, the host has a normal immune response and no immunosuppression-related infections, neoplasia, or other drug-related adverse effects. Rare cases of operational tolerance after transplantation, with complete cessation of immunosuppressive therapy (usually against medical advice), have been observed and reported.

Most studies of the intentional induction of immunologic tolerance have involved patients with hematologic malignancies. Full tolerance was achieved with myeloablative therapy before organ transplantation in combination with induced donor chimerism by means of bone marrow transplantation and excellent human leukocyte antigen (HLA) matching. Mixed chimerism retains a graft-versus-host T-cell effect that allows for transplant acceptance despite subsequent disappearance of the donor chimerism.

Myeloablative therapy includes total-body irradiation and lymphoablative methods, such as total lymphoid irradiation and use of azathioprine and corticosteroids. However, the complications of full tolerance and the untimeliness of donor organs with regard to preparation time for myeloablative therapy before transplantation preclude routine application of these therapies.

Cosimi and Sachs studied mixed chimerism in a small number of patients.² They used nonmyeloablative conditioning, such as peritransplantation low-dose total-body irradiation or thymic irradiation plus antithymocyte globulin therapy combined with splenectomy. Donor-specific marrow infusion was given at the time of transplantation. Cyclosporine was given for about a month after transplantation and then stopped. Patients had transient chimerism for several weeks, and graft survival was approximately 70% in the long term.

Bühler et al³ adopted this protocol for patients with multiple myeloma and end-stage renal disease who needed kidney transplantation (see Renal Transplantation [Urology] and Renal Transplantation [Medical]).³ However, they modified the regimen to replace total-body irradiation with 2 doses of cyclophosphamide 60 mg/kg given intravenously before transplantation, without splenectomy. Immunosuppressive therapy was withdrawn. No evidence of chronic rejection was observed in the longest surviving patient over 5 years.

This strategy was also attempted in patients with end-stage renal disease without malignancy who received HLA-mismatched kidneys. Although allograft tolerance due to mixed chimerism could be achieved in these patients, intense immunosuppression of humoral responses was necessary.

A caveat to these interesting reports is that some were described in meeting abstracts, and only some of the approaches have been reported in full papers.

Partial tolerance

At present, partial tolerance is more achievable than full tolerance. Partial tolerance is purported to occur with the use of initial intense immunosuppression that lowers the net amount of subsequent maintenance immunosuppressive medication, which might lower the long-term risks of infection, neoplasia, or drug-related adverse effects. This partial, or incomplete, donor-specific tolerance has been termed prope tolerance from the Latin word for near⁴ or minimal immunosuppression tolerance.⁵

Calne et al postulated that prope tolerance preserves some of the transplant recipient's immune responses to infection and other antigens, reducing morbidity and mortality due to immunosuppressive effects.⁶ In the late 1990s, his group reported 31 patients treated with alemtuzumab (Campath-1H) 20 mg given around the time of transplantation to reduce T and B cells by 1-2 logs. This was followed by half-dose cyclosporine monotherapy started on the third day. Trough cyclosporine levels were kept between 75 and 125 mg/dL. Twenty-nine patients had good graft function for over 5 years, and 3 had rejection needing additional immunosuppressive therapy. Six other steroid-responsive graft rejections were reported. Long-term results were similar to those observed in a comparator full-immunosuppression group.

Kirk et al sought to induce tolerance in renal allografts by inducing profound lymphocyte depletion with alemtuzumab (Campath-1H).⁷ This therapy achieved acute lymphocyte depletion but failed to induce tolerance. All patients had reversible rejection episodes in the first 3 weeks. They were characterized by predominant monocyte graft infiltration, and all were responsive to steroids and/or sirolimus. Reduced immunosuppression, usually with sirolimus, was continued without further episodes of rejection despite a recovery of normal lymphocyte counts.

Knechtle et al studied alemtuzumab (Campath-1H) and low-dose sirolimus.⁸ About 30% of kidney recipients had early rejection. Most cases were secondary to humoral responses.

Starzl, Shapiro, and colleagues compared alemtuzumab (Campath 1H) with tacrolimus monotherapy and reported a low rate of rejection episodes.

Given these data, alemtuzumab-related lymphocyte depletion at time of transplantation followed by calcineurin-inhibitor monotherapy (with either cyclosporine or tacrolimus) was a successful minimization strategy at 2 transplant centers. It did not increase rejection episodes and did not impair graft survival in the short-to-medium term.

Although researchers at numerous laboratories are investigating assays to monitor the degree of immunosuppression, no assays or tests are currently available to monitor tolerance. Identifying either prope or complete tolerance depends on the elimination, withdrawal, or reduction of maintenance immunosuppression and on the observation of a favorable response. Protocol allograft biopsy may or may not be helpful in identifying rejection at an early stage if the strategy is unsuccessful. Indeed, a specific directive of granting agencies, such as the National Institutes of Health and the Immune Tolerance Network, is to fund research to develop tolerance assays.

The demonstration of immune tolerance induction in many rodent models stands in stark contrast to the lack of success in humans and primates, with the exception of myeloablative therapy followed by donor-derived stem cell infusion. The specific pathogen–free environment in which rodents are housed for their lifetimes limits the number of memory T cells that such animals generate. On the other hand, humans and primates are exposed to many viruses during their long and less pathogen-free lives. In addition, they generate a considerable pool of self-renewing memory T cells (nearly half of circulating T cells in humans). Therefore, they are less immunologically naïve than experimental rodents. Many of these memory T cells can cross-react with foreign MHC. Therefore, the translation of tolerance induction strategies from the rodent laboratory to large animals and then to humans may need to account for previous specific and net immunologic memory.

REFERENCES

Section 6 of 6

• Authors and Editors
• Introduction
• Historical Background
• Mechanisms for Self-Tolerance
• Induction of Tolerance in Transplant Patients
• References

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Article Last Updated: Nov 30, 2007