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A Synthetic Random Basic Copolymer with Promiscuous Binding to Class II Major Histocompatibility Complex Molecules Inhibits T-Cell Proliferative Responses to Major and Minor Histocompatibility Antigens in vitro and Confers the Capacity to Prevent Murine Graft-Versus-Host Disease in vivo
Paul G. Schlegel, Rina Aharoni, Yanfei Chen, Jun Chen, Dvora Teitelbaum, Ruth Arnon, Michael Sela and Nelson J. Chao
Proceedings of the National Academy of Sciences of the United States of America
Vol. 93, No. 10 (May 14, 1996), pp. 5061-5066
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/38903
Page Count: 6
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Graft-versus-host disease (GVHD) is a T-cell-mediated disease of transplanted donor T cells recognizing host alloantigens. Data presented in this report show, to our knowledge, for the first time that a synthetic copolymer of the amino acids L-Glu, L-Lys, L-Ala, and L-Tyr (molecular ratio, 1.9:6.0:4.7:1.0; Mr, 6000-85000), termed GLAT, with promiscuous binding to multiple major histocompatibility complex class II alleles is capable of preventing lethal GVHD in the B10.D2 → BALB/c model (both H-2d) across minor histocompability barriers. Administration of GLAT over a limited time after transplant significantly reduced the incidence, onset, and severity of disease. GLAT also improved long-term survival from lethal GVHD: 14/25 (56%) of experimental mice survived >140 days after transplant compared to 2/26 of saline-treated or to 1/10 of hen egg lysozyme-treated control mice (P < 0.01). Long-term survivors were documented to be fully chimeric by PCR analysis of a polymorphic microsatellite region in the interleukin 1β gene. In vitro, GLAT inhibited the mixed lymphocyte culture in a dose-dependent fashion across a variety of major barriers tested. Furthermore, GLAT inhibited the response of nylon wool-enriched T cells to syngeneic antigen-presenting cells presenting minor histocompatibility antigens. Prepulsing of the antigen-presenting cells with GLAT reduced the proliferative response, suggesting that GLAT inhibits antigen presentation.
Proceedings of the National Academy of Sciences of the United States of America © 1996 National Academy of Sciences