Structures recognized during GVHD or graft rejection

ABO blood groups

A and B blood groups are recognized by natural antibodies in patients that are negative for the respective blood group. Therefore, patients are never transplanted with organs expressing incompatible AB molecules. HSCT do not express ABO molecules and although theoretically the B cells co-transfused with the HSC graft could continue to produce natural antibodies against the blood group of the recipient, in practice this rarely occurs at an extent that this represents a problem. Furthermore, the new B cells originating from the transplanted HSC that might produce natural antibodies against the incompatible blood groups on the recipients tissues will be deleted (tolerized) in the bone marrow like in normal individuals. Hence, reactions to (recognition of) ABO blood groups should not represent a problem in clinical transplantation and the molecules recognized during GVHD or organ rejections are the major or minor histocompatibility antigens.

Major Histocompatibility molecules recognized by alloantibodies (B cell response)

In organ transplantation where the recipients immune system is still functional, the chance exists that when the immunosuppression is too low, an antibody response against a mismatched MHC-molecule occurs (minor histocompatibility antigens are not recognized by antibodies). Furthermore, the immune system of the recipient may have been sensitized to the mismatched MHC-molecule by a previous transplantation, a blood transfusion or a pregnancy. In this case, the alloantibodies may exist already before the transplantation and may cause an acute rejection of the graft. To detect existing alloantibodies, a crossmatch test is performed.

Alloantibodies do not play a significant role in HSCT. Because the conditioning in recipients of HSC-grafts eradicates the recipient B cells and like for the natural antibodies, the transfused donor B cells are silenced, no antibodies against a mismatched MHC-molecules are produced.

B cell alloresponses are T cell dependent and cannot occur without priming of alloreactive T cells.

T cell responses

Although in principal T cells may react to the same alloantigens in organ transplantation as in HSCT, in practice the responses are different because the degree of matching between stimulator and responder is quite different. Most donor recipient pairs in HSCT are 100% MHC-compatible and the only incompatibilities that can be recognized are the minor histocompatibility antigens. By contrast, the recipient of an organ is seldom compatible with the donor and because the immune system usually responds to the "strongest" antigen (immunodominance), the initial response will almost always be against a mismatched MHC molecule while the additional minor antigens are ignored. Furthermore, because the frequency of T cells can recognize the mismatched MHC-molecule directly is much higher than the frequency of T cells that recognize the MHC-molecule through indirect recognition, the majority of the initial response will use the direct way of recognition.

There are many particularities that determine which antigen is recognized during rejection of an organ. The degree of matching, the immune suppression, the presence of APC's in the graft are all parameters that determine the type of alloresponse. Hence, numerous scenario's are possible and it is easily understood why the alloresponse keeps puzzling the transplantation immunologist.