Therapy with regulatory T-cell infusion in autoimmune diseases and organ transplantation: A review of the strengths and limitations.

In the last decade, cell therapies have revolutionized the treatment of some diseases, earning the definition of being the "third pillar" of therapeutics. In particular, the infusion of regulatory T cells (Tregs) is explored for the prevention and control of autoimmune reactions and acute/chronic allograft rejection. Such an approach represents a promising new treatment for autoimmune diseases to recover an immunotolerance against autoantigens, and to prevent an immune response to alloantigens. The efficacy of the in vitro expanded polyclonal and antigen-specific Treg infusion in the treatment of a large number of autoimmune diseases has been extensively demonstrated in mouse models. Similarly, experimental work documented the efficacy of Treg infusions to prevent acute and chronic allograft rejections. The Treg therapy has shown encouraging results in the control of type 1 diabetes (T1D) as well as Crohn's disease, systemic lupus erythematosus, autoimmune hepatitis and delaying graft rejection in clinical trials. However, the best method for Treg expansion and the advantages and pitfalls with the different types of Tregs are not fully understood in terms of how these therapeutic treatments can be applied in the clinical setting. This review provides an up-to-date overview of Treg infusion-based treatments in autoimmune diseases and allograft transplantation, the current technical challenges, and the highlights and disadvantages of this therapeutic approaches."

Investigation of the Association Between ITPA Gene 94C>A Sequence Variant and Kidney Transplant Rejection in Iranian Kidney Transplant Recipients.

OBJECTIVES: Thiopurine prodrugs are commonly used in kidney transplant recipients. Inosine triphosphate pyrophosphatase is an enzyme encoded by the ITPA gene. Alteration of ITPA gene is one of the pharmacogenetic sequence variants possibly involved in thiopurine metabolism. The ITPA 94C>A sequence variant (C-to-A substitution at nucleotide 94) is associated with an increased risk of adverse drug reactions in patients treated with the thiopurine drug. The aim of the present study was to investigate the effect of the ITPA 94C>A gene sequence variant in kidney transplant recipients. MATERIALS AND METHODS: The genotyping of the ITPA rs1127354 variant was performed by the polymerase chain reaction restriction fragment length polymorphism method in 140 kidney transplant recipients and in 100 control participants. Data were analyzed with SPSS statistical software. RESULTS: The results revealed a significant difference between control and nonrejection groups regarding the rs1127354 genotype and allele frequency. No significant difference was found between the rejection and nonrejection groups regarding the rs1127354 genotype and allele frequency. Also, a significant association was observed between the ageofthe control group and age of the rejection group. No significant differences between sex and underlying disease in patients with or without rejection were observed. CONCLUSIONS: We observed no significant differences between rejection and nonrejection transplant. Further studies are recommended, in a larger population and with different ethnicities.

The effects of metformin monotherapy and combination of metformin and glibenclamide therapy on the expression of RAGE, Sirt1, and Nrf2 genes in peripheral blood mononuclear cells of type 2 diabetic patients.

Purpose: Although metformin is the first-line treatment of type 2 diabetes mellitus (T2DM), a few studies have evaluated the benefits of monotherapies (metformin) versus combination therapy (metformin and glibenclamide) for treatment of T2DM patients. The present study aimed to evaluate the effect of monotherapy with metformin compared to combination therapy with metformin and glibenclamide on the expression of RAGE, Nrf 2, and Sirt1genes. Methods: EightyT2DM patients and 40 healthy individuals participated in this case-control study. The patients in the treatment group were divided into two groups who received either metformin alone (n = 40) or metformin in combination with glibenclamide (n = 40). FBS, HbA1c, and fructosamine were measured. The expression of RAGE, Nrf 2, and Sirt 1 genes in PBMC of all subjects were assessed using real-time PCR. Results: RAGE gene expression in both treatment groups was significantly lower than the control (P < 0.05). RAGE gene expression was significantly reduced in the combination of metformin and glibenclamide treated group compared to metformin group (P < 0.05). Additionally, the expression of Sirt 1 and Nrf 2 genes in both treatment groups was higher than that of the control group (P < 0.05). The expression of Sirt 1 and Nrf 2 genes in metformin and glibenclamide treated group were higher than the metformin group (P < 0.05). Conclusion: Combination therapy (metformin and glibenclamide) showed stronger effect on repression of the RAGE gene and activation of Nrf 2 and Sirt 1 genes compared to monotherapy (metformin); therefore, it can be concluded that combination therapy may have more protective effects on the T2DM patients. No significant correlation was observed between HbA1c and RAGE, Sirt 1, and Nrf 2 genes expression.

An Investigation of the Association Between Vascular Endothelial Growth Factor +405 G/C Polymorphism and Acute Liver Transplant Rejection in Iranian Liver Transplant Recipients.

OBJECTIVES: Vascular endothelial growth factor is an endothelial-specific growth factor that promotes endothelial cell proliferation, differentiation, and survival; mediates endothelium-dependent vasodilatation; induces microvascular hyperpermeability; and participates in interstitial matrix remodeling. The aim of the present study was to investigate the association between +405 G/C polymorphism of vascular endothelial growth factor and the risk of liver rejection in liver transplant recipients. MATERIALS AND METHODS: The present study included 124 patients with liver disease that led to liver transplant. There were 22 patients who experienced histologically proven acute liver rejection, and the other 102 patients showed no rejection. Both groups were matched for sex and age. The VEGF+405 G/C polymorphism was evaluated by the polymerase chain reaction-restriction fragment-length polymorphism method. RESULTS: Our analyses showed no significant relationships between genotypes and alleles of +405 G/C and risk of acute liver transplant rejection. CONCLUSIONS: Our report indicated that there was no association between the carrier states of +405 G/C gene polymorphism of vascular endothelial growth factor and acute rejection or nonrejection of liver transplant.

Investigation of the Association Between the ITPA Gene 94C>A Gene Sequence Variant and Liver Transplant Rejection in Iranian Liver Transplant Recipients.

OBJECTIVES: Inosine triphosphate pyrophosphatase is an enzyme encoded by the ITPA gene and functions to prevent the incorporation of thiopurine nucleotides into DNA and RNA. Thiopurine drug metabolites such as azathioprine and 6-mercaptopurine have been included in the lists of inosine triphosphate pyrophosphatase substrates. Inosine triphosphatase gene alterations are other pharmacogenetic sequence variants possibly involved in thiopurine metabolism. This study aimed to evaluate the possible association between ITPA 94C>A gene sequence variant (C-to-A substitution at nucleotide 94) in liver transplant recipients. MATERIALS AND METHODS: The genotyping of ITPA 94C>A was evaluated by the polymerase chain reaction- restriction fragment length polymorphism method in 200 liver transplant recipients as well as 100 controls. Data were analyzed with SPSS statistical software. RESULTS: This study showed statistically significant associations between the CA genotype of the ITPA 94C>A sequence variant and liver transplant in the rejection and nonrejection groups. Moreover, the results reported in this study showed no significant differences between sex, age, and blood group in patients with liver transplant (with or without transplant rejection). CONCLUSIONS: Our results indicated that there were statistically significant associations of the CA genotype of ITPA 94C>A sequence variant with liver transplant in the rejection and nonrejection groups. Further studies are recommended.

Gene Expression of Toll-Like Receptors 2 and 4 in Renal Transplant Rejection.

OBJECTIVES: Toll-like receptors are a crucial part of the innate immune system and have a pivotal role in the acquired immunity system. Studies have shown that Toll-like receptors 2 and 4 are important during the transplant process. Therefore, we analyzed the gene expression of Toll-like receptors 2 and 4 in cases of renal transplant rejection. We measured the messenger RNA expression levels of Toll-like receptors 2 and 4 in renal transplant rejection recipients compared with nonrejection recipients. MATERIALS AND METHODS: We enrolled 151 deceased-donor kidney transplant recipients, whom we divided into 2 groups: 101 nonrejection recipients and 50 recipients with acute allograft rejection. We collected 3 mL of blood (treated with ethylenediaminetetraacetic acid) from each patient. Ribonucleic acid extraction and complementary DNA synthesis were conducted for all samples, and the constructed complementary DNAs were used for real-time polymerase chain reaction analysis. RESULTS: We measured gene expression levels of Toll-like receptors 2 and 4 in renal transplant recipients with acute allograft rejection and in recipients who did not experience acute renal allograft rejection, and the results showed that messenger RNA expression levels for both Toll-like receptors 2 and 4 were significantly increased in the acute rejection group compared with the nonrejection group. CONCLUSIONS: Toll-like receptors 4 and 2 could increase the risk of acute rejection after renal transplant and could be defined as a risk factor for rejection. Further studies are recommended.