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.
Tao
H R
HR
Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
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