Inhibition of Pim2-prolonged skin allograft survival through the apoptosis regulation pathway

Abstract

Recently, apoptosis has been considered to be an important regulator for allograft survival. The serine/threonine kinase Pim2 has been implicated in many apoptotic pathways. In a previous study, we found that pim2 was highly expressed in CD4 1 T cells in an allograft model. Here, we further investigated the effects of Pim2 on allograft survival and the underlying mechanisms associated with apoptosis. The results showed that pim2 was overexpressed in grafts and spleens, particularly in spleen CD41 T cells when acute allorejection occurred, and correlated positively with the extent of rejection. In T cells from the spleens of naive BALB/c mice treated with 5 mM 4a (a specific inhibitor of Pim2) for 24 h, the apoptosis rate increased and the phosphorylation of BAD was decreased. Furthermore, adoptive transfer of CD41 T cells treated with 4a in vitro to allografted severe combined immunodeficiency (SCID) mice effectively prolonged allograft survival from 19.561.7 days to 3162.3 days. Moreover, the results demonstrated that the CD4 1 CD252 effector T-cell subset was the predominate expresser of the pim2 gene as compared with the CD4 1 CD25 1 regulatory T (Treg) cell subset. Alloantigen-induced CD4 1 CD25 1 T cells displayed less Foxp3 expression and a low suppression of apoptosis compared with effector CD41 CD25 2 T cells treated with 4a. Collectively, these data revealed that Pim2 facilitated allograft rejection primarily by modulating the apoptosis of effector T cells and the function of Treg cells. These data suggested that Pim2 may be an important target for in vivo anti-rejection therapies and for the ex vivo expansion of CD4 1 CD25 1 T cells.

Heme oxygenase-1-transduced bone marrow mesenchymal stem cells in reducing acute rejection and improving small bowel transplantation outcomes in rats

“…7b); in particular, Ad/HO-1/BMMSC treatment significantly decreased cell apoptosis in the graft mucosa. Acute rejection is associated with increased apoptosis in the graft [36, 37]. The amount of apoptotic body in crypts was one of the criteria for diagnosing the grade of acute rejection in SBTx [35].…”

Autophagy in Immune-Related Renal Disease

“…Pim-2, a Pim family kinase, is found in alloreactive effector T cell and favors its survival and proliferation [62]. It was reported that the Pim-2 level was positively correlated with the severity of allograft rejection and that inhibition of Pim-2 prevented the rejection [63]. Interestingly, T cell regulation, which leads to immune tolerance, is found to be associated with autophagy.…”

rFliC prolongs allograft survival in association with the activation of recipient Tregs in a TLR5-dependent manner

“…Our preliminary work also indicates that CD4 1 CD25 1 Tregs are associated with generegulated allorejection. 2 Ectopic expression of Foxp3 in mouse CD4 1 T cells induces the generation of nTregs in vitro [3][4][5] that results in a developmental transition to a suppressor cell phenotype, such as CD4 1 CD25 2 Foxp3 1 cells, which have been shown to be immune response suppressive. 6 Therefore, Foxp3 is considered a definitive lineage marker of nTregs.…”