Synergic silencing of costimulatory molecules prevents cardiac allograft rejection.

BACKGROUND: While substantial progress has been made in blocking acute transplant rejection with the advent of immune suppressive drugs, chronic rejection, mediated primarily by recipient antigen presentation, remains a formidable problem in clinical transplantation. We hypothesized that blocking co-stimulatory pathways in the recipient by induction of RNA interference using small interference RNA (siRNA) expression vectors can prolong allogeneic heart graft survival. METHOD: Vectors expressing siRNA specifically targeting CD40 and CD80 were prepared. Recipients (BALB/c mice) were treated with CD40 and/or CD80 siRNA expression vectors via hydrodynamic injection. Control groups were injected with a scrambled siRNA vector and sham treatment (PBS). After treatment, a fully MHC-mismatched (BALB/c to C57/BL6) heart transplantation was performed. RESULT: Allogeneic heart graft survival (>100 days) was approximately 70% in the mice treated simultaneously with CD40 and CD80 siRNA expression vectors with overall reduction in lymphocyte interstitium infiltration, vascular obstruction, and edema. Hearts transplanted into CD40 or CD80 siRNA vector-treated recipients had an increased graft survival time compared to negative control groups, but did not survive longer than 40 days. In contrast, allogenic hearts transplanted into recipients treated with scrambled siRNA vector and PBS stopped beating within 10-16 days. Real-time PCR (RT-PCR) and flow cytometric analysis showed an upregulation of FoxP3 expression in spleen lymphocytes and a concurrent downregulation of CD40 and CD80 expression in splenic dendritic cells of siRNA-treated mice. Functional suppressive activity of splenic dendritic cells (DCs) isolated from tolerant recipients was demonstrated in a mixed lymphocyte reaction (MLR). Furthermore, DCs isolated from CD40- and CD80-treated recipients promoted CD4+CD25+FoxP3+ regulatory T cell differentiation in vitro. CONCLUSION: This study demonstrates that the simultaneous silencing of CD40 and CD80 genes has synergistic effects in preventing allograft rejection, and may therefore have therapeutic potential in clinical transplantation.

Simultaneous pancreas-kidney transplantation: The role in the treatment of type 1 diabetes and end-stage renal disease.

Type 1 diabetes mellitus (DM) is one of the most common and debilitating diseases to affect the world. Many patients are afflicted by microvascular and macrovascular complications, and succumb to end-stage renal disease (ESRD). Although dialysis and insulin therapy provides better glycemic control, it nonetheless significantly decreases a patient's quality of life. Moreover, they cannot reverse ESRD or alleviate complications. Simultaneous pancreas-kidney (SPK) transplantation has revolutionized the way we manage type 1 DM; it provides a physiological means of achieving normoglycemia while rendering patients free of dialysis. Understanding this procedure is important because it is becoming a more common management strategy for patients with type 1 DM. In this review, we will begin with a brief summary of type 1 DM, followed by a comprehensive description of SPK procedure, including the history and technique. We will then present the outcomes of transplantation.