Synthesis of xenoantibodies at the gene and molecular level

The development of effective strategies to prevent the rejection of xenografts will require new approaches to preventing host humoral responses to the grafts. The evidence accumulated to date suggests that host antibody responses to xenografts are more difficult to control than the rejection reactions mounted against comparable allografts. Current methods of immunosuppression that might be used to prevent the cellular and humoral responses to xenograft produce serious side effects in experimental animals, indicating that the margin of safety for their use as a routine therapy in patients may be very narrow. Accordingly, understanding the precise mechanisms by which the host mounts a rejection reaction to the graft may provide new directions for the development of more effective and safer therapies to prolong graft survival. Examination of the structural and functional characteristics of the immunoglobulin genes used to encode xenoantibody activity has demonstrated that many characteristics of this component of the host response to xenografts are unique. The number of immunoglobulin genes used to encode antibodies directed against the grafts is relatively small. In the early stages of the response, they are expressed in their original germline configuration, and, as the response matures evidence for the use of both germline and antigen-driven Ig gene expression begins to appear. The response is encoded by variable region genes that display significant similarities in the amino acid residues found in specific sites within antibody combining sites, suggesting the evolutionary conservation of the Ig genes that control the xenoantibody response.