CTLA-4.FasL inhibits allogeneic responses in vivo.
CTLA-4.Fas ligand (CTLA-4.FasL), a paradigmatic 'trans signal converter protein (TSCP)', can attach to APC (via CTLA-4 binding to B7) and direct intercellular inhibitory signals to responding T cells (via FasL binding to Fas receptor), converting an activating APC-to-T cell signal into an inhibitory one. Our previous studies established that CTLA-4.FasL inhibits human primary mixed lymphocyte reactions (MLR) and induces alloantigen-specific hyporesponsiveness ex vivo. The present study extends this to an in vivo context. Using splenocytes from MHC-mismatched C57BL/6 and Balb/c mice, we demonstrated that his(6)CTLA-4.FasL, effectively inhibits murine MLR. Moving in vivo, we demonstrated that subcutaneously administered his(6)CTLA-4.FasL modulates the in vivo response of infused allogeneic splenocytes. his(6)CTLA-4.FasL reduces the number of cells in each cell division, and increases the percentage of dead cells in each division. These findings are consistent with an antigen-induced cell death of the alloreactive cells, and bolsters recombinant TCSP promise as a therapeutic for transplantation diseases.
Dranitzki-Elhalel
M
M
Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. michalelhalel@gmail.com
Huang
J-H
JH
Rachmilewitz
J
J
Pappo
O
O
Parnas
M
M
Schmidt
W
W
Tykocinski
M L
ML
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage* / Q000009:adverse effects / Q000502:physiology; D060908:CTLA-4 Antigen; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D053222:Fas Ligand Protein; D006131:Growth Inhibitors / Q000008:administration & dosage* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D019169:Jurkat Cells; D007959:Lymphocyte Culture Test, Mixed; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D019463:Mice, Inbred MRL lpr; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D048069:Tumor Necrosis Factors / Q000008:administration & dosage* / Q000009:adverse effects / Q000502:physiology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D048069:Tumor Necrosis Factors