A reliable non-invasive assay of immune responsiveness would help to predict the development of chronic rejection, stable function or tolerance in transplant recipients. Our aim is to develop novel non-invasive immune assays that allow either corrective changes in immunosuppressive regimens or in the planning of withdrawal of immunosuppressive medications. Renal allograft recipients (n=77) were screened starting at least 6 months after transplantation. All patients were on calcineurin-based immunosuppressive protocols consisting of cyclosporine (CsA)/mycophenolate mofetil (MMF)/steroid or tacrolimus (Tac)/MMF/steroid. Patients with biopsy proven chronic allograft dysfunction (CAD) with an elevated serum creatinine of ≥1.6 mg/dl were compared with patients with stable function (Cr <1.6 mg/dl). The frequency of IFN-γ and IL-10 producing PBMC in response to donor derived MHC class II peptide (indirect alloreactive T cells) were measured by Elispot. Sera were analyzed (16 cytokine panel) by Luminex to study pro-/anti-inflammatory cytokines that can differentiate chronic rejectors from patients with stable function. From a total of 77 patients, more patients on Tac/MMF/steroids had stable allograft function (n=20/30, 66.7%) as compared to patients receiving CsA/MMF/steroids (n= 21/47, 44.7%). Of all the patients in the CAD group a total of 24/36 patients had biopsy proven CR. Indirect Elispot revealed significantly higher IFN-gamma producing cells among chronic rejectors as compared to patients with stable allograft function. In contrast, patients with stable function produced significantly higher IL-10. Chronic rejectors showed higher IL-2, -6, -17, IFN-g, and lower IL-1Ra/IL-1b and TNF-RI/TNF-a ratios when compared to patients with stable function, suggestive of an ongoing active alloimmune process. In contrast, tolerant patients had significantly higher IL-4, -5, -10, and -13, predominantly anti-inflammatory cytokines. IL-10 and IFN-gamma indirect Elispot and the balance of pro-to anti-inflammatory cytokines may be useful tools in differentiating patients with worsening graft function from patients with stable allograft function. These results may provide an invaluable tool in assessing immunosuppressive status and tailoring immunosuppressive medications including withdrawal in tolerance trials.

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