sirolimus and Substance-Withdrawal-Syndrome

Diagnosis of immunologic injury (acute and chronic) is much more difficult in pancreas transplants when compared with transplants of other organs. Currently, the immunosuppressive regimen for induction involves calcineurin inhibitors (CNI), antimetabolites and corticosteroids (Cs). This strong and nonspecific regimen does not take into consideration pancreas specificities (i.e. the need to avoid diabetogenic compounds). For obvious reasons, CNI might be calling for review, if permanently indicated in recipients of solitary pancreas with mild renal dysfunction. CNI as well as corticosteroids may induce hyperglycemia and contribute to differential diagnosis of a rejection process. However, in spite of the benefits accruing from withdrawal of above immunosuppressive agents, minimization or avoidance of these drugs could be dangerous and may end up with graft loss (i.e. antibody-mediated process). Long-term results of pancreas transplantation are now achieving comparable survival rates similar to the transplant of traditional organs such as kidney and liver. As a consequence, the physicians' objectives are to prolong the patient's quality of life and organ function as long as possible. Weaning strategies in regard to CNI and steroids are tested. Sirolimus, everolimus, CTLA-4 Ig, etc, are agents known to be either both nonnephrotoxic and nondiabetogenic or less so when compared with CNI. Their impact on pancreas transplantation is beginning to be evaluated. Large randomized trials in all pancreas categories, with long-term clinical and histologic results, are mandatory to establish new guidelines for immunosuppressive regimens for pancreas transplantation.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Everolimus; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Sirolimus; Substance Withdrawal Syndrome; Tacrolimus

Topics: Adrenal Cortex Hormones; Azathioprine; Blood Pressure; Cyclosporine; Diabetes Mellitus; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lipid Metabolism; Sirolimus; Substance Withdrawal Syndrome; Transplantation Immunology

The mammalian target of rapamycin is an evolutionarily conserved serine-threonine kinase (mTOR), which controls protein synthesis and catabolism in response to environmental cues. This randomized double-blind clinical trial enrolled 60 abstinent heroin addicts and randomly assigned them to three groups: placebo, 2.5 mg and 5 mg rapamycin. The participants were given the cue-reactivity paradigm with 5 min exposures to neutral and drug-related imagery while craving, anxiety, blood pressure and heart rate pre- and post-exposure were assessed. We found that drug-related cues increased both craving and anxiety of abstinent heroin addicts, and had no effect on blood pressure and heart rate. A single high-dose of rapamycin significantly reduced the craving, but not anxiety induced by drug-related cues. Our findings suggested that rapamycin merits outpatient clinical trials as a potential pharmacotherapy for relapse prevention from drug-related cue induced craving.

Topics: Adult; Anxiety; Blood Pressure; Cues; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Rate; Heroin Dependence; Humans; Immunosuppressive Agents; Male; Sirolimus; Substance Withdrawal Syndrome

Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease.. Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward.. All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (+/-SE) donor-recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3+/-8.6% and 83.3+/-10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0+/-0.3 and 12.6+/-0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient.. A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor-recipient chimerism and reverse the sickle cell phenotype. (ClinicalTrials.gov number, NCT00061568.)

Topics: Adolescent; Adult; Alemtuzumab; Anemia, Sickle Cell; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antigens, CD34; Antineoplastic Agents; Clinical Protocols; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hemoglobins; Histocompatibility Testing; Humans; Leukocyte Count; Male; Middle Aged; Narcotics; Neutrophils; Sirolimus; Substance Withdrawal Syndrome; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation; Young Adult

This observational study was conducted to evaluate the safety and efficacy of the conversion from calcineurin inhibitors (CNIs) to sirolimus (SRL)-based immunosuppressive therapy in kidney transplantation.. Sixty-four kidney recipients of mean age 38.3 +/- 14.6 years were converted to SRL. The main reasons for conversion were elective in 45 (70.3%) and biopsy-proven chronic allograft nephropathy in 11 (17.2%). The primary CNI used was cyclosporine A in 51 patients. Mean time to conversion was 50.5 months. After conversion, 61 patients received mycophenolate mofetil. We evaluated the impact of conversion on renal function for 5 years post-conversion. The overall mean follow-up time was 72.8 months.. The analysis showed significant improvement in renal function at month 3 post-conversion (P < 0.05) with stabilization thereafter. Lipid parameters and blood sugar levels were similar pre- and post-conversion. Abnormal liver function test was transient in 12.8%. Reasons for SRL discontinuation were nephrotic range proteinuria in two patients and mouth ulceration in one. We compared patients with serum creatinine <140 micromol/l and those with serum creatinine > or = 140 micromol/l, and found that serum creatinine was an independent risk factor for chronic allograft dysfunction (P = 0.02). Graft loss occurred in three patients because of cardiovascular death in two and an acute rejection episode in one.. We concluded that conversion from CNIs to SRL is an option and of benefit without significant acute rejection episodes or chronic allograft dysfunction especially in well-selected kidney transplant recipients with good graft function.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Sirolimus; Substance Withdrawal Syndrome

In murine models, mixed hematopoietic chimerism induction leads to robust immune tolerance. However, translation to primates and to patients has been difficult. In this study, we used a novel MHC-defined rhesus macaque model to examine the impact of MHC matching on the stability of costimulation blockade-/sirolimus-mediated chimerism, and to probe possible mechanisms of bone marrow rejection after nonmyeloablative transplant. Using busulfan-based pretransplant preparation and maintenance immunosuppression with sirolimus, as well as CD28 and CD154 blockade, all recipients demonstrated donor engraftment after transplant. However, the mixed chimerism that resulted was compartmentalized, with recipients demonstrating significantly higher whole blood chimerism compared to T cell chimerism. Thus, the vast majority of T cells presenting posttransplant were recipient-rather than donor-derived. Surprisingly, even in MHC-matched transplants, rejection of donor hematopoiesis predominated after immunosuppression withdrawal. Weaning of immunosuppression was associated with a surge of antigen-experienced T cells, and transplant rejection was associated with the acquisition of donor-directed T cell alloreactivity. These results suggest that a reservoir of alloreactive cells was present despite prior costimulation blockade and sirolimus, and that the post-immunosuppression lymphocytic rebound may have lead to a phenotypic shift in these recipient T cells towards an activated, antigen-experienced phenotype, and ultimately, to transplant rejection.

Topics: Animals; Busulfan; Female; Graft Rejection; Hematopoietic Stem Cell Transplantation; Histocompatibility; Immune Tolerance; Immunosuppression Therapy; Macaca mulatta; Major Histocompatibility Complex; Male; Sirolimus; Substance Withdrawal Syndrome; T-Lymphocytes; Transplantation Chimera; Transplantation Conditioning