Transplantation Immunity

Transplant rejection within the same species is largely a consequence of MHC-restricted T-cell recognition of foreign MHC antigens. Interspecies re­jection is additionally contributed to by antibodies, and intolerance between complement activation mechanisms. Methods for reducing, or preventing, rejection include general immunosuppression, tolerance induction by means of cell chimerism, and sequestering of the transplanted cells or organ.

The strong transplantation antigens are encoded within the MHC complex, whilst the weak antigens constitute the MHC-presented allelic dif­ferences of non MHC-encoded host proteins or peptides. It is possible to differ­entiate between the host-versus-graft (HVG) reaction of the recipient against a genetically foreign tissue or organ, and the graft-versus-host (GVH) reaction.

The GVH reaction. This type of reaction results when immunologically respon­sive donor T cells are transferred to an allogeneic recipient who is unable to reject them (e.g., following a bone marrow transplant into an immunoincompetent or immunosuppressed recipient). The targets against which the transplanted T cells generate an immune response include the MHC class I and II molecules of the recipient. The recipient's transplantation antigens also present allelic variants of recipient self-peptides, which can be recog­nized by donor T cells as weak transplantation antigens when presented by common MHC alleles (it is conceivable that strong recipient transplanta­tion antigens could be accepted and processed by donor APCs, however even if this did occur it would be of limited functional consequence as they would not be presented by the recipient APC in the correct antigen configuration). Weak histocompatibility antigens—for instance those peptide variants recog­nized as nonself when presented in combination with essentially histocompatible MHC molecules—play a more significant role in bone marrow trans­plants. The existence, and pathological role, of weak transplantation antigens has only been demonstrated in completely histocompatible siblings or within inbred animal strains with identical MHC. The wide variety of alloreactive T cells can be explained by cross-reactivity, as well as by the enormous num­ber of different combinations of MHC molecules and cellular peptides. It must be emphasized that allogeneic MHC antigens on APCs and lymphocytes (so- called passenger lymphocytes) derived from the donor organ are particularly immunogenic since they express high levels of antigens and can traffic to To avoid a GVH reaction in immunoincompetent or suppressed bone mar­row recipients, immunocompetent T cells must first be eliminated from the transplanted bone marrow. This can be achieved by using anti-T-cell antibo­dies, anti-lymphocyte antisera, and complement or magnetic bead cell-separation techniques. However, it is noteworthy that complete elimination of mature T cells leads to a reduction in the acceptance rate for bone marrow transplants, and that it may also weaken the anti-tumor effect of the trans­plant (desirable in leukemia). It seems that the small number of Tcells trans­planted with the bone marrow can mediate a subclinical GVH reaction, thus preventing rejection of the transplant but retaining the ability to destroy the recipient's leukemia cells and preventing tumor re-emergence.

HVG reactions, that is immune responses of the recipient against trans­planted cells or organs, are not generated in autotransplants (for instance transplantation of skin from one part of the body to another on the same individual). This also applies to transplants between monozygotic twins or genetically identical animals (syngeneic transplants). However, transplants between non-related or non-inbred animals of the same species (allogeneic transplants), and transplants between individuals of different species (xeno­geneic transplants) are immunologically rejected. Because T cells recogni­tion is subject to MHC restriction, cellular rejection within a species is even more pronounced than between different species, although the latter procedure involves other transplantation complications. These include the occurrence of natural cross-reactive antibodies, and a lack of complement in­activation by anti-complement factors (which are often species-incompatible and therefore absent in xenogeneic transplants), which together often results in hyperacute rejection within minutes, hours, or a few days—that is before any specific immune responses can even be induced.

Three types of transplant rejection have been characterized:

-Hyperacute rejection of vascularized transplants, occurring within min­utes to hours and resulting from preformed recipient antibodies reacting against antigens present on the donor endothelium, resulting in coagulation, thromboses, and infarctions with extensive necrosis.

-Acute rejection, occurring within days or weeks. This is accompanied by a perivascular and prominent occurrence of T lymphocyte infiltrates. Acute re­jection can be prevented by immunosuppression.

-Chronic rejection, occurring within months to years. This is caused by low-level chronic T-cell responses, and can be mediated by cellular and hu­moral mechanisms. This can include obliterative vascular intima prolifera­tion, vasculitis, toxic, and immune complex glomerulonephritis.

Methods of measurement. The main methods used for follow-up analysis of HVG and GVH reactions are biopsies and histological evaluation, evaluation of blood cells and in-vitro mixed lymphocyte reactions.

References

Zinkernagel, R. M. (2005). Medical Microbiology. Thieme.