FK506 inhibits severe graft-versus-host disease without mediating the involvement of perforin and granzyme B.
FK506 treatment markedly increased survival rates of [BALB/c-->C3H/He] bone marrow and spleen (BM/Spl) chimeras which had severe graft-versus-host disease (GVHD), marking 91% survival rates on day 60. In contrast, none of the vehicle-treated allogeneic BM/Spl chimeras survived more than 43 days after bone marrow transplantation (BMT). All the [BALB/c-->C3H/He] bone marrow (BM) chimeras survived more than 60 days after BMT, regardless of FK506 treatment. Alloreactive mixed lymphocyte reactions (MLRs) against alloantigens in donor, host, and third party on week 8 were markedly inhibited in the spleen cells from all the chimeras including [C3H/He-->C3H/He] (syngeneic) BM chimeras. On week 12, alloreactive MLRs were still low in FK506-treated allogeneic BM/Spl and BM chimeras although those against third party alloantigen in the spleen cells from vehicle-treated allogeneic BM chimeras and syngeneic BM chimeras gradually recovered. Somewhat nonspecific cytotoxic activities against these alloantigens were sometimes observed, especially in week 8. Mitogen-induced responses confirmed that the immunosuppressive activity of FK506 was directed to T cells, since concanavalin A (ConA)- and phytohemagglutinin (PHA)-induced responses were completely inhibited, but lipopolysaccharide (LPS)- and pokeweed mitogen (PWM)-induced responses were not. Reverse-transcription polymerase chain reaction (RT-PCR) method suggested that perforin and granzyme B gene expressions were basically unchanged or rather increased in the spleen cells from FK506-treated allogeneic BM/Spl and BM chimeras. These gene expressions suggested that FK506 exerted its immunosuppressive effect in murine allogeneic bone marrow chimeras without mediating perforin and granzyme B.
Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
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Tao
D000818:Animals; D016026:Bone Marrow Transplantation; D003602:Cytotoxicity, Immunologic; D006086:Graft vs Host Disease / Q000188:drug therapy*; D053804:Granzymes; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D054353:Perforin; D010835:Phytohemagglutinins / Q000494:pharmacology; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D010835:Phytohemagglutinins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; D016559:Tacrolimus