FTY720 inhibits TH1-mediated allogeneic humoral immune response.
Phosphorylated FTY720 is an analog of Sphingosine 1 Phosphate (S1P) with immunosuppressive activity that negatively regulates the expression of S1P-Receptor 1. It also inhibits the migration of CD4 and CD8 single-positive T cells from the thymus to the periphery, sequesters peripheral blood lymphocytes in lymph nodes and Peyer's patches, and delays the exit of effector T cells toward the graft. The aim of our work was to study the effect of FTY720 on the kinetics of skin allograft rejection in a fully mismatched model; euthymic (Euthy) versus thymectomized (ATX) C57BL/6 mice (haplotype H-2(b)) recipients of BALB/c mice (haplotype H-2(d)) donor cells. The animals were injected daily with FTY720 (1 mg/kg) intraperitoneally for 2 weeks. To monitor the humoral immune response, serum samples collected at day 0 (pre-immune) and at day 23 after skin graft rejection were examined using BALB/c thymocytes as antigens in flow cytometry. To confirm the effect of FTY720 on peripheral lymphocytes, peripheral blood was analyzed by flow cytometry. Euthy and ATX FTY720-treated mice showed prolongation of skin allograft survival when compared with nontreated Euthy and ATX controls (P < .005). Unexpectedly, FTY720-treated Euthy mice showed significantly delayed graft rejection when compared to similarly treated ATX mice (P < .005). The delayed graft rejection in FTY720-treated Euthy mice correlated with a reduced content of Th1-mediated IgG(2a) and IgG(2b) antibodies when compared with FTY720-treated ATX mice (P < .05). In conclusion, FTY720 delays the kinetics of allograft rejection in a fully mismatched model by inhibiting Th1-mediated humoral immune responses. The presence of the host thymus appears to be required for this phenomenon.
Peñuelas-Rivas
G
G
Unit of Transplantation Research, Experimental Surgery, Arrixaca University Hospital, Murcia, Spain.
Domínguez-Perles
R
R
Brinkmann
V
V
Del Rio
M L
ML
Muñoz-Luna
A
A
Ramírez-Romero
P
P
Parrilla-Paricio
P
P
Rodríguez-Barbosa
J I
JI
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D005260:Female; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011409:Propylene Glycols / Q000494:pharmacology*; D016038:Skin Transplantation / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives; D013934:Thymectomy; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology*
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine