Effect of CD80 and CD86 blockade and anti-interleukin-12 treatment on mouse acute graft-versus-host disease.
We investigated the efficacy of a combination of anti-CD80 and CD86 (CD80 + 86) monoclonal antibodies (mAb), anti-interleukin (IL)-12 mAb, or both, for prophylaxis in a mouse acute graft-versus-host-disease (GVHD) model. The treatment with a combination of anti-CD80 + 86 mAb efficiently reduced the lethality of GVHD, whereas mAb against either CD80 or CD86 alone had an effect. A delay in lymphocyte reconstitution and GVHD-associated histological changes in organs was observed at 30 days post-bone marrow transplantation (BMT) even in the anti-CD80 + 86 mAb-treated mice, although these manifestations were resolved by 100 days. In vitro, host alloantigen-specific T cell proliferative responses and generation of CTL were significantly reduced by anti-CD80 + 86 treatment. Furthermore, anti-CD80 + 86 mAb preferentially inhibited the production of interferon (IFN)-gamma, but not IL-4 and IL-10, when cultures were assayed at 21 days. Although the anti-IL-12 mAb treatment alone inhibited the generation of cytotoxic T lymphocytes and IFN-gamma production in vitro, administration of anti-IL-12 mAb in vivo reversed the beneficial effects of anti-CD80 + 86 treatment on host survival post-BMT. The adverse effect of anti-IL-12 treatment seems to result from impairment of natural immunity and hematopoiesis, rather than as a consequence of an incomplete blockade of T helper (Th)1 responses. Our results suggest that the prevention of GVHD-induced death results from the efficient blockade of Th1 cell activation by the anti-CD80 + 86 treatment. However, further treatment is required for a complete prevention of GVHD, which seems to be partly mediated by Th2 cells.
Saito
K
K
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Yagita
H
H
Hashimoto
H
H
Okumura
K
K
Azuma
M
M
D000208:Acute Disease; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control* / Q000628:therapy*; D007116:Immunization, Passive; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma