Combined costimulation blockade inhibits accelerated rejection mediated by alloantigen-primed memory T cells in mice.
Donor-reactive memory T cells threaten the survival of transplanted organs via multiple pathways. This study was undertaken to induce tolerance of cardiac allografts in mice, in which alloreactive memory T cells were adoptively transferred, by combined costimulatory blockade of both effector and memory T cells. We found that the median survival time (MST) of the grafts was 5.17 days in the untreated group, 10.33 days in the CTLA4Ig- and anti-CD40L-treated (2-combined) group, and more than 100 days in the CTLA4Ig-, anti-CD40L-, anti-LFA-1-, and anti-OX40L-treated (4-combined) group. Histological analysis revealed that the mean rejection level was Grade 4 in the untreated group, Grade 3 in the 2-combined treatment group, and Grade 0 in the 4-combined treatment group. CD44(high) T cells were detected only in the untreated group. The in vitro proliferation of lymphocytes of both untreated and 2-combined group was higher than that of the 4-combined treatment group (p < 0.01). Compared with the untreated group, the expression levels of IL-2, IFN-gamma, and Foxp3 were lower in the 2-combined treatment group; the expression levels of these genes were the lowest in the 4-combined treatment group. IL-10 expression was significantly higher in the 4-combined treatment group than in the other groups. These results demonstrate the inhibition efficacy of combined costimulation blockade in accelerated-rejection models and the possible mechanisms underlying the suppression of cellular immunity in mice receiving grafts as well as in inducing the activation of IL-10-producing Tr1 cells in grafts.
Xie
Baiyi
B
Organ Transplantation Institute, Xiamen University, Fujian Province, PR China.
Chen
Jibing
J
Xia
Junjie
J
Wang
Yongzhi
Y
Liang
Hua
H
Ekberg
Henrik
H
Corbascio
Matthias
M
Qi
Zhongquan
Z
D000069594:Abatacept; D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology; D018960:Hyaluronan Receptors / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D018796:Immunoconjugates / Q000008:administration & dosage / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018960:Hyaluronan Receptors; D018796:Immunoconjugates; D007376:Interleukin-2; D007519:Isoantigens; D016169:Lymphocyte Function-Associated Antigen-1; D053278:OX40 Ligand; D023201:CD40 Ligand; D000069594:Abatacept; D007371:Interferon-gamma