Role for thymic and splenic regulatory CD4+ T cells induced by donor dendritic cells in allograft tolerance by LF15-0195 treatment.
A 20-day treatment with LF15-0195, a deoxyspergualine analogue, induced allograft tolerance in a fully MHC-mismatched heart allograft model in the rat. Long-term allografts displayed minimal cell infiltration with no signs of chronic rejection. CD4+ spleen T cells from tolerant LF15-0195-treated recipients were able to suppress in vitro proliferation of allogeneic CD4+ T cells and to transfer tolerance to second syngeneic recipients, demonstrating dominant suppression by regulatory cells. A significant increase in the percentage of CD4+CD25+ T cells was observed in the thymus and spleen from tolerant LF15-0195-treated recipient. In vitro direct stimulation with donor APCs demonstrated that CD4+ regulatory T cells proliferated weakly and expressed low levels of IFN-gamma, IL-10, and IL-2. CD4+CD25+ cell depletion increased IL-2 production by CD4+CD25- thymic cells, but not splenic cells. Moreover, tolerance was transferable with splenic and thymic CD4+CD25+ cells, but also in 50% of cases with splenic CD4+CD25- cells, demonstrating that CD25 can be a marker for regulatory cells in the thymus, but not in the periphery. In addition, we presented evidences that donor APCs were required to induce tolerance and to expand regulatory CD4+ T cells. This study demonstrates that LF15-0195 treatment induces donor APCs to expand powerful regulatory CD4+CD25+/- T cells present in both the central and peripheral compartments.
Chiffoleau
Elise
E
Institut National de la Santé et de la Recherche Médicale Unité 437, 30 boulevard Jean Monnet, 44093 Nantes Cedex 01, France.
Bériou
Gaëlle
G
Dutartre
Patrick
P
Usal
Claire
C
Soulillou
Jean-Paul
JP
Cuturi
Maria Cristina
MC
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006146:Guanidines / Q000008:administration & dosage*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D018796:Immunoconjugates; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D007399:Interphase / Q000187:drug effects / Q000276:immunology; D007518:Isoantibodies / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013154:Spleen / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology; D018800:Thy-1 Antigens / Q000096:biosynthesis; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D016207:Cytokines; D006146:Guanidines; D018796:Immunoconjugates; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007518:Isoantibodies; D007519:Isoantigens; C434185:LF 150195; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D000069594:Abatacept; D007371:Interferon-gamma