Amelioration of acute graft-versus-host disease and re-establishment of tolerance by short-term treatment with an anti-TCR antibody.
We investigated whether tolerance can be re-established in mice with graft-vs-host disease (GVHD) by using a short-term, T cell-depleting treatment with an anti-TCR-alpha beta mAb. GVHD was induced in 950-rad-irradiated AKR mice (H-2k, Mls-1a) by injecting 5 x 10(6) T cell-depleted bone marrow cells together with either 10(7) or 2 x 10(6) lymph node (LN) cells from BALB/c mice (H-2d, and Mls-1b). AKR mice that received 10(7) LN cells exhibited a severe form of acute GVHD, in which all mice died by day 60. In this severe form of GVHD, treatment with anti-TCR-alpha beta mAb completely ameliorated the induction of GVHD when initiated on day 0 (a total of 800 micrograms/mouse administered on days 0,5, and 10). When the same protocol was begun on day 10, it had no therapeutic effect. However, this delayed treatment with anti-TCR-alpha beta mAb was very effective in reversing a less severe form of GVHD that was induced by the injection of 2 x 10(6) donor LN cells. Recipient mice given prophylactic anti-TCR-alpha beta treatment achieved host-specific tolerance in association with clonal deletion of host Mls-1a-reactive V beta 6+ T cells. In contrast, spleen cells from recipient mice that recovered from the mild form of GVHD as a result of the delayed anti-TCR-alpha beta treatment contained a considerable proportion of the V beta 6+ T cells, despite the healthy appearance of these mice. A MLR assay revealed that the spleen cells from these mice responded well to Mls-1a Ag but not to H-2k Ag, in contrast with the apparent responses of spleen cells from untreated GVHD controls to both Ags. In addition, cells from the anti-TCR-alpha beta-treated mice exhibited a specific reduction in cytotoxicity against AKR blasts. Collectively, these data indicate that a short-term treatment of mice having GVHD with an anti-TCR-alpha beta mAb, starting even after disease onset, can re-establish host-specific tolerance, at least to the host-histo-compatibility Ag.
Maeda
T
T
Department of Immunology, Kyushu University, Fukuoka, Japan.
Eto
M
M
Lin
T
T
Nishimura
Y
Y
Kong
Y Y
YY
Nomoto
K
K
Nomoto
K
K
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy*; D006183:H-2 Antigens / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008815:Mice, Inbred Strains; D016747:Minor Lymphocyte Stimulatory Antigens / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; D016747:Minor Lymphocyte Stimulatory Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta