| Research Abstract |
Transplantation is one of the optimal treatments for patients possessing non-functional cells, tissues, and organs. However, a variety of host immune cells infiltrating into the transplantation site recognize the allografts as non-self to kill them (allograft rejection). Human MHC class I genes (human leukocyte antigen : HLA) are contained in the A, B, and C regions ; and there are 30, 60, and 10 haplotypes, respectively, assuming that 1 of 20000 donors might have MHC class I molecules identical to those of a recipient. Right now, the recipient continues to take nonspecific immunosuppressive medicine. Sometimes, it causes recipient death by infection as a side effect. The dream on transplantation therapy is to inhibit the allograft rejection, a physiological immune response, without any side effects. There are 2 ways to achieve it : one is isolation of cDNAs encoding receptors for MHC class I molecules and identification of their ligands. The other one is specific inhibition of the int
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eraction between an MHC class I molecule and its receptor without any side effects in a tailor-made manner. In 2006, we isolated 2 cDNA clones encoding novel MHC receptors on allograft-induced macrophages (AIM) for allogeneic MHCs (i.e., H-2D^d and H-2K^d) by using anti-AIM monoclonal antibodies (R15 and R12) and allogeneic MHC tetramers (H-2D^d and H-2K^d). We called these 2 receptors macrophage MHC receptor 1 (MMR1) and MMR2, respectively. In 2010, we isolated a cDNA encoding a human homologue (83.6% amino acid identity) of mouse MMR2 from a human cDNA library, the donors of which had never been allografted, and identified HLA-B62 as a possible ligand for human MMR2 on monocytes. Recently, we also isolated a cDNA encoding a human homologue of mouse MMR1 from a human cDNA library, and identified a possible ligand for human MMR2 on monocytes. Furthermore, in order to know the physiological significance of these MHC class I molecules and their receptors, we established D^d, K^d or D^d,K^d transgenic mice or tumor cells, and transplanted the transgenic skin onto or transgened tumor cells into C57BL/6 mice. The results clearly showed transgene number-dependent, gene expression rate-independent rejection of D^d-, K^d-, or D^dK^d-transgened mouse skin or tumor cells from C57BL/6 (D^bK^b) mice. Using MMR KO mice, finally, we will know the physiological significance of MMRs. On the other hand, in order to develop a new type of medicine that inhibits the interaction between an MHC class I molecule and its receptor, we asked Protein Science Institute Co. to identify the peptide sequences which might suppress the interaction, asked a company to synthesize those peptides, and established MMR-transgened cells by our selves. The binding assay of H-2K^d pentamer to MMR2-transgened EL-4 cells and the effects of 4 kinds of peptides on the interaction are under investigation. Meantime, we realized that an MMR is very specific for an MHC class I molecule and that human or mouse might have several 10 kinds of MMRs for all non-self MHC class I molecules. Therefore, if we could isolate cDNAs for 8 kinds of HLA-A and 9 kinds of HLA-B and if we could develop a new type of medicine to inhibit the interaction of MMRs with MHC class I molecules, we might be able to regulate allograft rejection without any side effects in a tailor-made manner. Less
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