Strategies to overcome hyperacute rejection of pig-to-human xenografts.
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Acute Disease↗
Biomedical subjects
M S Sandrin
Publications and source records attributed to M S Sandrin.
Genetic engineering for xenotransplantation.
Xenotransplantation is being pursued vigorously to solve the shortage of allogeneic donor organs. Experimental studies of the major xenoantigen (Gal) and of complement regulation enable model xenografts to survive hyperacute rejection. When the Gal antigen is removed or reduced and complement activation is controlled, the major barriers to xenograft survival include unregulated coagulation within the graft and cellular reactions involving macrophages, neutrophils, natural killer (NK) cells, and T lymphocytes. Unlike allografts, where specific immune responses are the sole barrier to graft survival, molecular differences between xenograft and recipient that affect normal receptor-ligand interactions (largely active at the cell surface and which may not be immunogenic), are also involved in xenograft failure. Transgenic strategies provide the best options to control antigen expression, complement activation, and coagulation. Although the Gal antigen can be eliminated by gene knockout in mice, that outcome has only become a possibility in pigs due to the recent cloning of pigs after nuclear transfer. Instead, the use of transgenic glycosyl transferase enzymes and glycosidases, which generate alternative terminal carbohydrates on glycolipids and glycoproteins, has reduced antigen in experimental models. As a result, novel strategies are being tested to seek the most effective solution. Transgenic pigs expressing human complement-regulating proteins (DAF/CD55, MCP/CD46, or CD59) have revealed that disordered regulation of the coagulation system requires attention. There will undoubtedly be other molecular incompatibilities that need addressing. Xenotransplantation, however, offers hope as a therapeutic solution and provides much information about homeostatic mechanisms.
Animals↗
Serological analysis of H-2 mutations using monoclonal antibodies.
Nine H-2Kb and H-2Db mutants were examined for serological differences from the wild type C57BL/6 using a panel of monoclonal antibodies (mAbs). Several differences (between the Kb mutants) were established with these mAbs. The bm3 and bm11 mutants could be distinguished serologically even though they have very similar amino acid changes. Conversely, the bm 1 and bm 10 mice, which differ in their sites of Kb mutation, express a common serological mutation, suggesting that tertiary conformation is involved in antibody binding. Both bm13 and bm14 (H-2Db mutants) exhibited profound serological alterations in H-2Db molecules when tested with mAbs that bind determinants mapping to both the NC1 and C2M domains of the Db molecule. In addition, bm13 showed altered binding of two anti-H-2Kb monoclonals.
Amino Acid Sequence↗