Nidyanandh Vadivel

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

BACKGROUND AND OBJECTIVESnNearly 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.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnThis 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.nnnRESULTSnA 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.nnnCONCLUSIONSnThis 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.

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)-&agr; 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)-1&bgr;, IL-6, and TNF-&agr; (r>0.8, P<0.001 for all correlations). The levels of these cytokines were associated with transplant glomerulopathy (IL-1&bgr;, P=0.019; IL-6, P=0.015; and TNF-&agr;, P=0.006) but not with other chronic lesions or anti-HLA circulating alloantibodies. TNF-&agr; was predominantly secreted by monocytes (percent of TNF-&agr; 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.

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.

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.