Epigallocatechin-3-gallate maintains Th1/Th2 response balance and mitigates type-1 autoimmune diabetes induced by streptozotocin through promoting the effect of bone-marrow-derived mesenchymal stem cells.

Stem-cell-based therapy is one of the most promising therapeutic strategies owing to its regenerative and immunomodulatory properties. Epigallocatechin-3-gallate (EGCG), a known antioxidant and anti-inflammatory agent, has beneficial effects on cellular protection. We aimed to elucidate the feasibility of using EGCG, along with bone marrow-derived mesenchymal stem cells (BM-MSCs), to improve pancreatic damage through their immune regulatory functions in an experimental model of type 1 diabetes mellitus (T1DM) induced by multiple injections of streptozotocin (STZ). BM-MSCs were isolated from C57BL/6 mice and characterized. The diabetic groups were treated intraperitoneally with PBS, MSCs, EGCG, and a combination of MSCs and EGCG. Real-time PCR assays showed that MSCs with EGCG modulated T-bet and GATA-3 expression and upregulated the mRNA levels of Foxp-3 more efficiently. Analyses of spleen-isolated lymphocytes revealed that combinational treatment pronouncedly increased regulatory cytokines and decreased pro-inflammatory cytokines and splenocyte proliferation. The histopathological assessment demonstrated that co-treatment significantly reduced insulitis and recovered pancreatic islet morphology. Furthermore, the combination of MSCs and EGCG is associated with downregulated blood glucose and enhanced insulin levels. Therefore, combined therapy with EGCG and MSCs holds clinical potential for treating T1DM through synergetic effects in maintaining the Th1/Th2 response balance and promoting the regeneration of damaged pancreatic tissues.

CTLA4-Ig alleviates the allogeneic immune responses against insulin-producing cells in a murine model of cell transplantation.

The adoptive transfer of insulin-producing cells (IPCs) is one of the promising treatments for insulin-dependent diabetes mellitus. While the use of allogeneic cell resources is inevitable in the case of a series of patients, alloimmune responses are a major barrier ahead of the successful implementation of allogeneic therapeutic cells. This study is aimed at evaluating the potential of CTLA4-Ig, as an approved immunomodulatory biologic, in protecting the IPCs against allogeneic immune responses. The C57BL/6 and BALB/c mice were used to establish a murine model of allogeneic cell transplantation. The mouse bone-marrow-derived mesenchymal stem cells were in vitro differentiated into IPCs, and the in vitro as well as the in vivo immune responses against IPCs were evaluated in the presence and absence of CTLA4-Ig. The allogeneic IPCs induced the in vitro activation of CD4+ T-cells, IFN-γ release, and the proliferation of lymphocytes, which all were controlled by CTLA4-Ig. Upon in vivo transfer of IPC into an allogeneic host, the splenic CD4+ and CD8+ T-cells exhibited a significant activation, and there was a significant donor-specific antibody response. Either of the mentioned cellular and humoral responses were modulated by a CTLA4-Ig regimen. This regimen also reduced the infiltration of CD3+ T-cells into the IPC injection site along with the improved overall survival of diabetic mice. CTLA4-Ig could be a complementary therapy for improving the efficacy of allogeneic IPC therapy through modulating the cellular and humoral responses that can lead to prolonged durability of IPCs within an allogeneic host.

Evaluation of Inhibitory Effect of Abatacept (CTLA4-ig) and Conditioned Medium of Mesenchymal Stem Cell in an Acetic Acid-induced Mouse Model of Acute Colitis.

An individual with a genetic predisposition to inflammatory bowel disease (IBD) can experience inflammatory responses leading to conditions such as Crohn's disease (CD) or Ulcerative colitis (UC). Currently, stem cell therapies, particularly those utilizing mesenchymal stem cells (MSCs), are gaining attention due to their immunomodulatory properties, as demonstrated in clinical trials. Consequently, we decided to investigate the effects of mesenchymal stem cells-conditioned medium (MSC-CM) and Abatacept in an experimental model of acute colitis. MSC-CM was extracted from female BALB/C mice and stored for future use. Acute colitis was induced in BALB/C mice through the intrarectal administration of 100 µL of 4% acetic acid. Following this procedure, CM and Abatacept were administered intraperitoneally. Throughout the study, various parameters were monitored, including changes in body weight, bleeding, stool consistency, disease activity index (DAI), mortality rate, as well as the weight and length of the colon. Histopathological analyses were also conducted, along with monitoring changes in the levels of IL-10 and IFN-γ. The data collected are presented as mean ± SD and were analyzed using One-Way ANOVA. According to the results of the study, CM with and without Abatacept significantly reduced weight loss and bleeding as well as improved fecal consistency and DAI. Macroscopic examination of the colon showed that after infusion, colon length was reduced and histopathological analysis showed a decrease in mucosal changes. The secretion of IL-10 was increased while the IFN-γ level was reduced. Research indicates that the immunomodulatory properties of MSC secretion can have positive effects. We propose a combination therapy with MSC, which we believe could lead to improved outcomes in the treatment of acute colitis.