Studies on the mechanism and specificity of the effect of the synthetic random copolymer GLAT on graft-versus-host disease.
Graft-versus-host disease (GVHD), which occurs when donor T-cells recognize multiple minor host histocompatibility antigens as non-self, presents the major limitation to successful allogeneic bone-marrow transplantation. The synthetic random copolymer of the amino acids, L-Glu, L-Lys, L-Ala and L-Tyr, termed GLAT, with promiscuous binding to multiple MHC class II alleles, reduces the incidence, onset and severity of disease in the BIO.D2 --> BALB/c model of lethal GVHD. GLAT inhibited the proliferative response towards host of both spleen cells from mice with GVHD and also of the effector T cell line established from these mice. Administration of GLAT for a limited period after transplantation completely abolished the cytotoxic activity toward host cells exerted by spleen cells from mice with GVHD. Whereas spleen and bone marrow cells from control mice with GVHD secreted IL-2 and INF-gamma when cocultured with host cells, these inflammatory cytokines could not be detected in supernatants of cells from GLAT treated mice. Moreover spleens and bone marrow cells from GLAT treated mice secreted small but significant amounts of IL-4 and IL-6 when cocultured with GLAT, suggesting that GLAT not only inhibits pro-GVHD cytokines but also causes a beneficial effect by inducing secretion of Th2 type cytokines. GLAT binds strongly to MHC molecules of host as well as donor haplotype. D-GLAT, identical to GLAT but composed of D-amino acids is also effective in preventing GVHD. D-GLAT does not cross-react with L-GLAT, but still binds strongly to MHC-class II molecules. These findings indicate that MHC blocking is involved in the therapeutic effect of GLAT on GVHD. The cumulative data demonstrate that GLAT modulates the effector mechanisms involved in GVHD, and can be potentially used for the prevention of GVHD across minor histocompatibility barriers.
Aharoni
R
R
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Schlegel
P G
PG
Teitelbaum
D
D
Roikhel-Karpov
O
O
Chen
Y
Y
Arnon
R
R
Sela
M
M
Chao
N J
NJ
D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D011108:Polymers; D011828:Radiation Chimera; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010455:Peptides; D011108:Polymers; C021759:(T,G)-A-L; C020749:GAT; D007371:Interferon-gamma