Induction treatment with rabbit antithymocyte globulin versus basiliximab in renal transplant recipients with planned early steroid withdrawal.

STUDY OBJECTIVE: To compare the safety and efficacy of rabbit antithymocyte globulin (r-ATG) with basiliximab in renal transplant recipients for whom an early steroid withdrawal (ESW) regimen was planned. DESIGN: Single-center, retrospective, cohort study. SETTING: Tertiary care medical center, including inpatient hospital stays and outpatient nephrology clinics. PATIENTS: Ninety-nine consecutive adult recipients of living- or deceased-donor renal transplants between January 1, 2004, and December 31, 2007, in whom ESW was planned and who received either r-ATG or basiliximab; patients receiving an extended-criteria kidney donation or a donation after cardiac death were excluded. MEASUREMENTS AND MAIN RESULTS: All patients received mycophenolate mofetil and tacrolimus as maintenance therapy with planned ESW. Induction therapy was either r-ATG 1.5 mg/kg/day for 4 days (68 patients) or basiliximab 20 mg on postoperative days 0 and 4 (31 patients). The primary composite end point of biopsy-proven acute rejection (BPAR), graft loss, and death occurred in 6 patients (9%) and 9 patients (29%) in the r-ATG and basiliximab groups at 1 year after transplantation, respectively (p=0.01), with rates of 7% (5/68 patients) and 26% (8/31 patients) for BPAR (p=0.02), 0% and 3% (1/31 patients) for graft loss (p=0.31), and 2% (1/68 patients) and 0% for patient death (p>0.99). Average time to first BPAR was significantly longer in the r-ATG group (mean ± SD 151.4 ± 82.9 vs 53.6 ± 68.4 days, p<0.01). Kidney function at 12 months was similar between the two groups. CONCLUSION: Rabbit-ATG was associated with a lower frequency and delayed onset of BPAR compared with basiliximab in renal transplant recipients who received an ESW regimen.

Monocyte-secreted inflammatory cytokines are associated with transplant glomerulopathy in renal allograft recipients.

BACKGROUND: Although there is ample evidence about the role of adaptive immunity in the development of chronic allograft dysfunction, little is known about the contribution of innate immunity to this process. Herein, we studied the relationship between inflammation, chronic biopsy scores, and anti-human leukocyte antigen (HLA) circulating alloantibodies in a cohort of 57 patients recruited at our center. METHODS: Available biopsies (n=27) were graded for chronic lesion scores according to Banff criteria. The production of cytokines by peripheral blood mononuclear cells after 48 hr of culture under resting conditions was quantified by Luminex. Tumor necrosis factor (TNF)-α secretion assay and depletion studies were used to identify the source of these cytokines. RESULTS: There was a high correlation between the levels of interleukin (IL)-1ß, IL-6, and TNF-α (r>0.8, P<0.001 for all correlations). The levels of these cytokines were associated with transplant glomerulopathy (IL-1ß, P=0.019; IL-6, P=0.015; and TNF-α, P=0.006) but not with other chronic lesions or anti-HLA circulating alloantibodies. TNF-α was predominantly secreted by monocytes (percent of TNF-α secreting cells: 20.4±4.8 vs. 1.2±0.5 vs. 1.4±0.6 vs. 1.7±0.5 for CD14, CD4, CD8, and CD19 cells, respectively; all P<0.01 vs. CD14). The levels of all three proinflammatory cytokines were significantly reduced after monocyte depletion. Intriguingly, cytokine levels increased after ex vivo depletion of regulatory T cells (all P<0.001). CONCLUSIONS: Taken together, these data suggest that in vivo-activated monocytes in peripheral blood spontaneously secrete proinflammatory cytokines in renal allograft recipients with transplant glomerulopathy and seem to be under the regulation of functional regulatory T cells in this setting.

Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation.

BACKGROUND AND OBJECTIVES: Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed. RESULTS: A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia. CONCLUSIONS: This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.

Critical role of donor tissue expression of programmed death ligand-1 in regulating cardiac allograft rejection and vasculopathy.

BACKGROUND: Allograft vasculopathy is a major limiting factor in the long-term success of cardiac transplantation. T cells play a critical role in initiation of cardiac allograft rejection and allograft vasculopathy. The negative T-cell costimulatory pathway PD-1:PDL1/PDL2 (programmed death-1:programmed death ligand-1/2) plays an important role in regulating alloimmune responses. We investigated the role of recipient versus donor PD-1 ligands in the pathogenesis of allograft rejection with emphasis on the role of tissue expression in regulating this alloimmune response in vivo. METHODS AND RESULTS: We used established major histocompatibility complex class II- and class I-mismatched models of vascularized cardiac allograft rejection, blocking anti-PDL1 and anti-PDL2 antibodies, and PDL1- and PDL2-deficient mice (as donors or recipients) to study the role of the PD-1:PDL1/PDL2 pathway in chronic rejection. We also used PDL1-deficient and wild-type mice and bone marrow transplantation to generate chimeric animals that express PDL1 exclusively on either hematopoietic or parenchymal cells. PDL1 but not PDL2 blockade significantly accelerated cardiac allograft rejection in the bm12-into-B6 and B6-into-bm12 models. Although wild-type cardiac allografts survived long term, PDL1-/- donor hearts transplanted into wild-type bm12 mice exhibited accelerated rejection and vasculopathy associated with enhanced recipient T-cell alloreactivity. Interestingly, PDL1-/- recipients did not exhibit an accelerated tempo of cardiac allograft rejection. Using chimeric animals as donors, we show that PDL1 expression on cardiac tissue alone significantly prolonged graft survival compared with full PDL1-/- donor grafts in transplanted wild-type recipients. CONCLUSIONS: This is the first report to demonstrate that expression of the negative costimulatory molecule PDL1 on donor cardiac tissue regulates recipient alloimmune responses, allograft rejection, and vasculopathy.

Chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) remains the Achilles heel of renal transplantation. In spite of the significant strides achieved in one-year renal allograft survival with newer immunosuppressant strategies, the fate of long-term renal allograft survival remains unchanged. The number of renal transplant recipients returning to dialysis has doubled in the past decade. This is especially important since these patients pose a significantly increased likelihood of dying while on the waiting list for retransplantation, due to increasing disparity between donor organ availability versus demand and longer waiting time secondary to heightened immunologic sensitization from their prior transplants. In this review we analyze the latest literature in detail and discuss the definition, natural history, pathophysiology, alloantigen dependent and independent factors that play a crucial role in CAN and the potential newer therapeutic targets on the horizon. This article highlights the importance of early identification and careful management of all the potential contributing factors with particular emphasis on prevention rather than cure of CAN as the core management strategy.

Mechanisms of PDL1-mediated regulation of autoimmune diabetes.

The PD-1-PDL1 pathway plays a critical role in regulating autoimmune diabetes as blockade or deficiency of PD-1 or PDL1 results in accelerated disease in NOD mice. We explored the cellular mechanisms involved in the regulation of these autoimmune responses by investigations involving various gene-deficient mice on the NOD background. Administration of blocking anti-PDL1 antibody to CD4+ T cell-deficient, CD8+ T cell-deficient and B cell-deficient mice demonstrated that PDL1-mediated regulation of autoreactive CD4+ and CD8+ T cells is critical for diabetes development. This concept was confirmed by adoptive transfer studies utilizing lymphocytes from BDC2.5 and 4.1 (CD4+) TCR transgenic mice and 8.3 (CD8+) TCR transgenic mice; efforts showing increased proliferation of both CD4+ and CD8+ T cells following PDL1 blockade in vivo. Furthermore, we observed that anti-PDL1-mediated acceleration is dependent upon events occurring in the pancreatic lymph nodes during early disease stages, but becomes independent of the pancreatic lymph nodes during later disease stages. These data provide strong evidence that PDL1 regulates autoimmune diabetes by limiting the expansion of CD4+ and CD8+ autoreactive T cells, and define the timing and locale of PDL1-mediated regulation of type 1 diabetes.

Transplant tolerance through costimulation blockade--are we there yet?

Achieving a tolerant state specific to the transplanted graft without subjecting patients to the risks of non-specific immunosuppression is the goal of transplant immunologists. In spite of the success achieved with currently available immunosuppresive therapies over acute rejection, an ongoing T cell mediated alloimmune response still poses a major challenge to the health of an allograft through chronic rejection. Modulating these destructive alloresponses through T cell costimulation blockade is a promising area of interest. In this article, we review our current knowledge about the role of various positive and negative costimulatory pathways during an alloimmune response. The ultimate nature of that response depends on the complex interaction between these positive and negative costimulatory pathways. We discuss the progress that has been achieved so far, through targeting these individual pathways, their interaction with other costimulatory pathways and the currently available immunosuppressive agents in various organ transplant models.

BK viral reactivation in cardiac transplant patients: evidence for a double-hit hypothesis.

BACKGROUND: BK nephropathy is a significant cause of renal dysfunction in renal allograft recipients. The question of whether BK viral infection plays a role in renal dysfunction in cardiac transplantation patients remains to be answered. METHODS: We prospectively examined the prevalence of BK viral reactivation in the setting of cardiac transplantation and performed a cross-sectional analysis of 111 cardiac transplantation patients. We also assessed the prevalence of viremia in a cohort of 29 renal transplant recipients. RESULTS: We found urinary decoy cells in 28 cardiac transplantation patients. Of these, 14 patients had evidence of BK viral DNA in the urine. None, however, had evidence of BK viremia. Mean age, gender, levels of pre- and post-transplant serum creatinine, cardiopulmonary bypass time, and ischemic time were not significantly different between the groups. We found that 7 of 29 renal transplant recipients studied had BK viral DNA in their urine. CONCLUSION: These findings are evidence of BK virus reactivation in the setting of cardiac transplantation at a percentage similar to that seen in renal allograft recipients. In contrast to renal allograft recipients, none had evidence of viremia. Thus, even in the setting of established BK virus reactivation, immunosuppression in combination with renal allograft dysfunction and renal ischemic injury is usually insufficient to cause BK viremia and nephropathy, and it appears that a second, organ-specific hit is necessary, such as kidney inflammation, kidney ischemia, or donor-recipient human leukocyte antigen mismatch.