Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Abstract

Although current immunosuppression protocols improve the efficacy of clinical allogenic islet transplantation, T cell-mediated allorejection remains unresolved, and major histocompatibility complexes (MHCs) play a crucial role in this process. Papain, a cysteine protease, has the unique ability to cleave the extracellular domain of the MHC class I structure. We hypothesized that pretreatment of donor islets with papain would diminish the expression of MHC class I on islets, reducing allograft immunogenicity and contributing to prolongation of islet allograft survival. BALB/ c islets pretreated with papain were transplanted into C57BL/6J mice as an acute allorejection model. Treatment with 1 mg/mL papain significantly prolonged islet allograft survival. In vitro, to determine the inhibitory effect on T cell-mediated alloreactions, we performed lymphocyte proliferation assays and mixed lymphocyte reactions. Host T cell activation against allogenic islet cells was remarkably suppressed by pretreatment of donor islet cells with 10 mg/mL papain. Flow cytometric analysis was also performed to investigate the effect of papain treatment on the expression of MHC class I on islets. One or 10 mg/mL papain treatment reduced MHC class I expression on the islet cell surface. Pretreatment of donor islets with papain suppresses MHC class Imediated allograft rejection in mice and contributes to prolongation of islet allograft survival without administration of systemic immunosuppressants. These results suggest that pretreatment of human donor islets with papain may reduce the immunogenicity of the donor islets and minimize the dosage of systemic immunosuppressants required in a clinical setting.

Anakinra and Tocilizumab Enhance Survival and Function of Human Islets during Culture: Implications for Clinical Islet Transplantation

“…This is well in coherence with previous finding that islet viability and function wore protected by Anakinra 244 . Others have shown similar effects when pre-treating islets with other pro-inflammatory cytokine such as sulfhydryl protease, Papain, cleaving human leukocyte antigen class I from human lymphocytes 245 and an GLP-1 receptor agonist, exenatide 246 .…”

Withaferin A inhibits lymphocyte proliferation, dendritic cell maturation in vitro and prolongs islet allograft survival

“…Mixed lymphocyte reaction (MLR) was performed as described previously 50 . Human DC maturation assays were completed, with mature DCs generated as described previously 51 .…”

Poly (γ‐glutamic acid)/chitooligo‐saccharide/papain hydrogel prevents hypertrophic scar during skin wound healing

“…Papain was also reported to inhibit the MPAs formation‐mediated activation of monocytes via inhibiting the MAPKs and PI3K/Akt signal pathway 21 . even allograft islets‐induced T cells activation could be inhibited by10 mg/ml papain pre‐treatment 22 . Papain can significantly down‐regulate the expression of TGF‐β1 protein and the phosphorylation of Smad‐3, thus effectively regulating cell proliferation and the effect of cells and extracellular matrix by regulating the TGF‐β/Smad signaling pathway, and reducing collagen and keratin tissue located in the dermis 23 .…”