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.
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, 6000-8500) [corrected], 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 histocompatibility 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 1beta 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.
Schlegel
P G
PG
Bone Marrow Transplantation Program, Stanford University School of Medicine, CA 94305, USA.
Aharoni
R
R
Chen
Y
Y
Chen
J
J
Teitelbaum
D
D
Arnon
R
R
Sela
M
M
Chao
N J
NJ
D000818:Animals; D001483:Base Sequence; D002678:Chimera / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D006086:Graft vs Host Disease / Q000517:prevention & control*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000235:genetics; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology*
D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D007375:Interleukin-1; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D011108:Polymers