Recombinant IL-33 prolongs leflunomide-mediated graft survival by reducing IFN-γ and expanding CD4(+)Foxp3(+) T cells in concordant heart transplantation.
Interleukin (IL)-33 is a novel IL-1 family member, and its administration has been associated with promotion of T helper type-2 (Th2) cell activity and cytokines, particularly IL-4 and IL-5 in vivo. Recently, IL-33 was shown to increase CD4(+)Foxp3(+) regulatory T cells (Tregs) and to suppress levels of the Th1-type cytokine IFN-γ in allogeneic heart transplantation in mice. Therefore, we hypothesized that IL-33 and leflunomide (Lef) could prolong graft survival in the concordant mouse-to-rat heart transplantation model. In this model, xenografts undergo acute humoral xenograft rejection (AHXR) typically on day 3 or cell-mediated rejection approximately on day 7 if AHXR is inhibited by Lef treatment. Recipients were treated with Lef (n=6), IL-33 (n=6), IL-33 combined with Lef (n=6), or left untreated (n=6) for survival studies. Heart grafts were monitored until they stopped beating. Mouse heterotopic grafts were performed, and recipients were sacrificed on days 2 and 7 for histological and flow cytometric analyses. The combination of IL-33 and Lef significantly prolonged the grafts from 17.3±2.3 to 2.8±0.4 days, compared to untreated controls. IL-33 administration with Lef, while facilitating Th2-associated cytokines (IL-4 on day 2 but not day 7), also decreased IFN-γ on day 2 and day 7, compared with Lef treatment only. Furthermore, IL-33 with Lef administration caused an expansion of suppressive CD4(+)Foxp3(+) Tregs in rats. The IL-33 and Lef combination therapy resulted in significantly prolonged graft survival, associated with markedly decreased Th1 cells and increased IL-10 levels. In addition, the combination therapy significantly decreased the percentage of CD-45(+) B cells on days 2 and 7, compared with monotherapy. These findings reveal a new immunoregulatory property of IL-33. Specifically, it facilitates regulatory cells, particularly functional CD4(+)Foxp3(+) Tregs that underlie IL-33-mediated cardiac xenograft survival. Moreover, it can decrease Th1 cells and cytokine expression of Th1 T cells in xenograft recipients, for example IFN-γ.
Institute of Organ Transplantation, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of the Ministry of Education, Wuhan, Hubei, PR China.|Key Laboratory of Organ Transplantation of the Ministry of Health, Wuhan, Hubei, PR China.
Chen
C
Dai
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Fang-Na
FN
Lu
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Ning
N
Jin
Institute of Organ Transplantation, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of the Ministry of Education, Wuhan, Hubei, PR China.|Key Laboratory of Organ Transplantation of the Ministry of Health, Wuhan, Hubei, PR China.
Bo
B
Yang
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Chang
C
Gao
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Bin
B
Zhao
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Jia-Zhao
JZ
Fu
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Shi-Fu
SF
Hong
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Han-Ting
HT
Liang
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Li-Hong
LH
Chen
Institute of Organ Transplantation, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of the Ministry of Education, Wuhan, Hubei, PR China.|Key Laboratory of Organ Transplantation of the Ministry of Health, Wuhan, Hubei, PR China.
Zhi-Shui
ZS
Chen
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Jie
J
Chen
Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, PR China.
Zhong-Quan
ZQ
Qi
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation; D064593:Heterografts; D056724:Immunity, Humoral / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000378:metabolism; D000067596:Interleukin-33 / Q000008:administration & dosage*; D007555:Isoxazoles / Q000008:administration & dosage*; D000077339:Leflunomide; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000008:administration & dosage; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D007166:Immunosuppressive Agents; D000067596:Interleukin-33; D007555:Isoxazoles; D011994:Recombinant Proteins; D007371:Interferon-gamma; D000077339:Leflunomide