Host And Graft Adaptation

Synopsis: Despite immunosuppression, transplantation could not be successful if adaptive changes favoring prolonged graft survival did not occur in both the host and the graft. The adaptive changes in the graft may reflect the loss of the donor bone marrow-derived cells, with the loss of "signal 2". The antigen specific adaptive changes in the host are dependent on the continuous presence of the antigens of the graft — and on immunosuppressive therapy, in many or most patients. The host probably develops a state of partial peripheral tolerance.

Host Adaptation

The encounter of the immune system with antigen can result in a positive response, a negative response ("tolerance"), or no response ("neglect"), depending on the circumstances in which the antigen is presented. Tolerance is defined as a state of antigen-specific unresponsiveness induced by exposure to antigen, typically under conditions of immaturity, injury, or drug therapy. The ability to induce tolerance is vital for self and nonself discrimination and to randomly generate potentially autoreactive cells. T cell tolerance is classified by location: central versus peripheral.

Central Tolerance

The principal central mechanism of tolerance in the thymus during T-cell ontogeny is clonal deletion by apoptosis.203 Intrathymic injections of antigen can induce tolerance in rats, but these approaches have not yet been successful in primates.84,204 Central tolerance is believed to have little role in transplantation although microchimerism with donor cells could play a role centrally. In general, chimerism can induce tolerance only in significant levels, and microchimerism does not correlate with true tolerance.

Peripheral Tolerance

Successful transplantation involves a degree of peripheral tolerance. Studies of transgenic mice expressing foreign MHC antigens in peripheral tissues have recently been particularly helpful for understanding peripheral tolerance (reviewed in ref. 206). These and other models suggest several possible mechanisms:

First, in some models, clonal expansion then clonal deletion occurs, causing peripheral tolerance. This is particularly true for responses to "superantigens", which delete previously expanded clones as an outcome of powerful immune responses probably by programmed cell death.207 Lack of co-stimulatory signals (IL-1, adhesion molecules) may promote peripheral clonal deletion. Overall, however, peripheral clonal deletion is not a prominent mechanism.

Clonal anergy, i.e., paralysis without deletion, is demonstrable in some circumstances. In some MHC class I transgenic mice, tolerance is the result of anergy and is dependent on the continuous presence of Ag and the lack of IL-2.208 Exogenous IL-2 reverses the state of anergy. Some patients receiving long-term immunosuppression with functioning allografts simulate this state. In some models of MHC class II transgenic mice, T cells exhibit low reactivity against class II in vitro, with no in vivo pathology,209 a form of "neglect". IFN-y may abrogate some tolerant states.210 Cytokines of the TH2 type, e.g., IL-10, may suppress IL-2 and

IFN-y expression,211,212 but it is difficult to imagine long-term high levels of cytokine production as a mechanism for maintaining tolerance. Clinical immunosuppressive treatment, particularly with cyclosporine and steroid, may also act in this way, selectively reducing IL-2 and IFN-y production.

A variety of other mechanisms could be important:

1. Down-regulation of TCRs and co-receptors (CD4 or CD8);213

2. "Veto cells" (these are T cells which inactivate T cells which try to recognize them);214

3. Antigen-specific T cells actively maintaining unresponsiveness, especially CD4 T cells.215 CD4 T cells producing TH2 cytokines could decrease the production of TH1 cytokines from other lymphocytes in a "contagious" fashion;

4. Anti-idiotypes. Idiotypes are antigen combining sites, either of TCRs or antibodies, and anti-idiotypes are antibodies which are directed against them. The extensive literature on anti-idiotype antibodies and idiotype-specific regulatory T cells has not led to examples of negative regulation unequivocally mediated by an idiotype/anti-idiotype interaction. There is evidence for the role of anti-idiotypes in turning off anti-HLA antibody responses.216

Adaptive Changes in the Graft

With time, if the graft survives, the inflammation subsides, and the induced expression of adhesion molecules and MHC antigens in the graft returns toward normal. There is a progressive loss of the donor antigen presenting cells, replaced by the recipient cells. Thus both direct antigen presentation by donor cells and indirect presentation by host cells subside. Injuries, including ischemic and reperfusion injury, rejection, and viral infection, can promote inflammatory changes and sustain the immune process.217 The changes of inflammation and those of tissue repair in response to injury overlap. Immunologic and nonimmuno-logic injury can both therefore lead to a common pathway of chronic inflammation which manifests itself in sub-acute or chronic rejection. Thus injury may sustain the host APC and antigen expression burden of the graft, sustaining immunologic activity and preventing the stabilization of the host graft relationship.


The transfer of tissue from a donor to a recipient transfers some bone marrow-derived cells, some of which are stem cells. The donor bone marrow-derived cells can persist and establish bone marrow microchimerism, i.e., permanent persistence of small numbers of bone marrow derived stem cells of donor type, presumably due to establishment of a few donor stem cells. This would link transplantation-induced peripheral tolerance with classic neonatal tolerance in mice,218 which is probably a chimeric state. Microchimerism after blood transfusion may explain the well known blood transfusion effect and why matching of HLA antigens between the blood donor and recipient helps to establish the hyporesponsive state. Some long-term transplant recipients have evidence of microchimerism,219 even decades after the transplant. Persistent donor cells could be the result or the cause of host hyporesponsiveness. Microchimerism in long-term survivors could lead to central tolerance and clonal deletion by colonization of the host thymus by donor stem cells.

Implantation of allogeneic tissues in the thymus before allografting is an experimental strategy for inducing some central tolerance in rodents.220 It remains a challenge to demonstrate that this technique works in large animals and man.

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