Reactivation of BK virus (BKV) following renal transplantation (KTx) is common and can lead to BK virus- associated nephropathy (BKVN), a serious and increasing problem. Current therapeutic options are limited to tapering of immunosuppression and experimental use of cidofovir. Available evidence suggests that BKV- specific T-cell responses are important in controlling infection, and we hypothesize that viral reactivation in KTx drives the expansion of functional BK-specific cells which control BKV in the majority of patients, but in a minority, this immune response is absent or dysfunctional, which may predispose to progression to BKVN. If true, functional BKV-specific T-cells could represent correlates of protection against BKVN. We will test this hypothesis by using state-of-the-art flow cytometry methodologies to track and characterize BKV-specific T-cell responses in two cohorts of KTx patients at UCLA Medical Center. The first cohort will comprise 40 Ktx recipients who will be prospectively followed beginning 1 month and until 1 year post- transplant. A second cohort will consist of KTx patients with clinically confirmed BKVN and enrolled at the time of diagnosis. The patients will be monitored by plasma PCR for BKV viral load. Global analyses of immunological responses to BKV will consist of flow-based intracellular cytokine assays employing as antigens overlapping peptide libraries spanning the majority of the viral proteome. These will be supplemented by more sensitive immunological probes to a panel of immunodominant BKV T-cell epitopes we have previously identified. The functionality of these BKV-specific CD4 and CDS T-cells in terms of cytolytic potential and production of different cytokines will be characterized and correlated with viral load and clinical status to see if these cells represent markers for BKV reactivation and/or protection against BKVN. Immunological probes to detect these cells may form the basis for tests to guide clinical management. Relevance: With the increasing problem of Type II diabetes, the number of kidney transplants being performed within the US is rising. Although BK virus is ubiquitous in human populations and establishes a life-long infection, it is only life-threatening in the context of a minority of immunocompromised KTx recipients. Information from the proposed study may allow identification of patients at risk of progression from BKV reactivation to clinical BKV disease and guide therapeutic interventions. ? ? ?
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