The University of Wisconsin renal transplant program in December 2002 adopted an immunosuppressive strategy consisting of Campath-1H induction (30 mg i.v. times 2), and maintenance immunosuppression consisting of a calcineurin inhibitor, mycophenolate mofetil, and low-dose steroids (methylprednisolone 10 mg a day). We have witnessed approximately 5% incidence of rejection with very few side effects. In order to test the hypothesis that these patients would do well with subsequent withdrawal of calcineurin inhibitors, a clinical trial has been IRB approved at this center for randomization 1:1 to either continue or discontinue calcineurin inhibitors beginning at least 2 months post-transplant. Tapering would occur over 3 months. Based on preliminary results derived in our renal transplant population using Campath-1H induction, we are evaluating four mechanistic assays to determine their usefulness in assessing the immune status of renal transplant patients, that is, whether they are safe to reduce immunosuppression or at risk for rejection. This application seeks to fund these four mechanistic assays to determine their usefulness in association with this clinical trial of calcineurin inhibitor withdrawal. Whether or not the clinical trial is successful in freeing patients from calcineurin inhibitor use, data and methodology derived from these mechanistic assays would be applicable to a broad range of organ transplant recipients and would guide development of immunologic monitoring tools in the field of transplantation. The four specific aims of this application are: 1. To assess donor-specific unresponsiveness in patients using a CFSE-based proliferation assay and T-lymphocyte activation response profile. 2. To assess the alloantibody response following transplantation in study patients to determine whether it is predictive of graft outcome (acute and chronic rejection) and/or correlates with histologic injury in 1- and 2-year biopsies. 3. To assess development of T cell regulation in patients using the trans-vivo DTH assay and evaluation of TGF-beta expression in protocol biopsies at one and two years. 4. To assess putative genetic markers of tolerance by correlating their expression in blood and biopsy specimens at 1 and 2 years post-transplant with graft function, immunosuppressive drugs, and the measurements obtained in specific aims 1-3 above.
| Kwun, J; Oh, B C; Gibby, A C et al. (2012) Patterns of de novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment. Am J Transplant 12:2641-51 |
