Comparative Inhibitory Effects of Tacrolimus, Cyclosporine, and Rapamycin on Human Anti‐Pig Xenogeneic Mixed Lymphocyte Reactions

Author:

Zhang Man1234,Feng Hao1234,Du Jiaxiang5,Chen Song1234,Zhu Lan1234,Wang Yi67,Pan Dengke5ORCID,Chen Gang1234ORCID

Affiliation:

1. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China

2. Key Laboratory of Organ Transplantation Ministry of Education Wuhan China

3. NHC Key Laboratory of Organ Transplantation Wuhan China

4. Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China

5. Chengdu Clonorgan Biotechnology Co., Ltd Chengdu China

6. Department of Organ Transplantation The Second Affiliated Hospital of Hainan Medical University Haikou China

7. The Transplantation Institute of Hainan Medical University Haikou China

Abstract

ABSTRACTBackgroundLong‐term immunosuppressive maintenance therapy is necessary to prevent the rejection of xenografts. However, it is still unclear which oral immunosuppressant is most suitable for pig‐to‐human xenotransplantation .MethodsA xenogeneic mixed lymphocyte reaction (MLR) system was established using peripheral blood mononuclear cells (PBMCs) isolated from wildtype (WT) or GTKO/CMAHKO/β4GalNT2KO (TKO) pigs as stimulator cells and human PBMCs as responder cells. Various concentrations of tacrolimus (Tac), cyclosporine (CsA), or rapamycin (Rapa) were added to the MLR system as interventions. The inhibitory effects of the three immunosuppressants on the proliferation and cytokine production of human T cells were studied and compared. The inhibitory effect of anti‐CD154 mAb alone or in combination with Tac/CsA/Rapa on xenoreactive MLR was also investigated.ResultsPBMCs from both WT and TKO pigs stimulated significant proliferation of human T cells. Tac had a strong inhibitory effect on human T‐cell proliferation stimulated by pig PBMCs. CsA inhibited human T‐cell proliferation in a typical dose‐dependent manner. When Tac and CsA concentrations reached 5 and 200 ng/mL, respectively, the proliferation rates of CD3+/CD4+/CD8+ T cells were reduced almost to a negative level. Even at high concentrations, Rapa had only a moderate inhibitory effect on xenogeneic MLR. The inhibitory effects of these three immunosuppressants on xenogeneic T‐cell responses were further confirmed by the detection of CD25 expression and supernatant cytokines (IL‐2, IL‐6, IFN‐γ, TNF‐α, IL‐4, IL‐10, and IL‐17). Although anti‐CD154 mAb monotherapy showed only moderate inhibitory effects on xenoreactive T‐cell proliferation, low‐dose anti‐CD154 mAb combined with low‐dose Tac, CSA, or Rapa could produce significant synergistic inhibitory effects.ConclusionTac is more efficient than CsA or Rapa in inhibiting xenogeneic T‐cell responses in vitro. If used in combination with anti‐CD154 mAb, all the three immunosuppressants can achieve satisfactory synergistic inhibitory effects.

Funder

National Key Research and Development Program of China

Fundamental Research Funds for the Central Universities

Publisher

Wiley

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