sirolimus and tofacitinib

The success of solid-organ transplantation was made possible by recognizing that destruction of the graft is caused by an alloimmune-mediated process. For the past decade, immunosuppressive protocols have used a combination of drugs that significantly decreased the rate of acute organ rejection. Despite advances in surgical and medical care of recipients of solid-organ transplants, long-term graft survival and patient survival have not improved during the past 2 decades. Current immunosuppression protocols include a combination of calcineurin inhibitors, such as tacrolimus, and antiproliferative agents (most commonly mycophenolate mofetil), with or without different dosing regimens of corticosteroids. Mammalian target of rapamycin inhibitors were introduced to be used in combination with cyclosporine-based therapy, but they did not gain much acceptance because of their adverse event profile. Belatacept, a costimulatory inhibitor, is currently being studied in different regimens in an effort to replace the use of calcineurin inhibitors to induce tolerance and to improve long-term outcomes. Induction therapy is now being used in more than 90% of kidney transplants and more than 50% cases of other solid-organ transplantation such as lung, heart, and intestinal transplants. As a result of these combination immunosuppressive (IS) therapy protocols, not only the incidence but also the intensity of episodes of acute rejection have decreased markedly, and at present 1-year graft and patient survival is almost 98% for kidney transplant recipients and approximately greater than 80% for heart and lung transplants. Evolving concepts include the use of donor-derived bone marrow mesenchymal cells to induce tolerance, to minimize the use of maintenance IS agents, and to prevent the development of adverse events associated with long-term use of maintenance IS therapy.

Topics: Abatacept; Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Azathioprine; Bone Marrow Transplantation; Calcineurin Inhibitors; Cyclosporine; Disease Models, Animal; Everolimus; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lung Transplantation; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Tacrolimus

The last several decades have seen a substantial decrease in the prevalence of acute allograft rejection in kidney transplant recipients, while equivalent improvements in long-term graft function have not been realized. As a result, the primary focus of new immunosuppressive drug development has expanded to include ease of use, improved side effect profiles, and reduced nephrotoxicity in addition to the more traditional goal of improved short-term outcomes. A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. ISA247 (voclosporine) is a cyclosporine (CsA) analog with reduced nephrotoxicity in Phase III study. AEB071 (sotrastaurin), a protein kinase C inhibitor, and CP-690550, a JAK3 inhibitor, are small molecules in Phase II studies. Everolimus is derived from the mTOR inhibitor sirolimus and is in Phase III study. Belatacept is a humanized antibody that inhibits T-cell costimulation and has shown encouraging results in multiple Phase II and III trials. Alefacept and Efaluzimab are humanized antibodies that inhibit T-cell adhesion and are in Phase I and II clinical trials. This article reviews the mechanisms of action as well as published and preliminary results of the Phase I-III clinical trials involving these novel immunosuppressive agents.

Topics: Abatacept; Alefacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cyclosporine; Everolimus; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Piperidines; Pyrimidines; Pyrroles; Quinazolines; Recombinant Fusion Proteins; Sirolimus

Topics: Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Juvenile; Child; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Methotrexate; NF-KappaB Inhibitor alpha; Piperidines; Pyrimidines; Severity of Illness Index; Sirolimus; Treatment Failure; Tumor Necrosis Factor Inhibitors

Antibody-mediated response in solid organ transplantation is critical for graft dysfunction and loss. The use of immunosuppressive agents partially inhibits the B-lymphocyte response leading to a risk of acute and chronic antibody-mediated rejection. This study evaluated the impact of JAK3 and PKC inhibitors tofacitinib (Tofa) and sotrastaurin (STN), respectively, on B-cell proliferation, apoptosis, and activation in vitro.. Human B cells isolated from peripheral blood of healthy volunteers were cocultured with CD40 ligand-transfected fibroblasts as feeder cells in the presence of interleukin (IL) 2, IL-10, and IL-21. The cocultures were treated with immunosuppressants Tofa, STN, and rapamycin (as a control), to analyze the proliferation and apoptosis of B cells by means of Cyquant and flow cytometry, respectively. CD27 and IgG staining were applied to evaluate whether treatments modified the activation of B cells.. Tofa and STN were able to inhibit B-cell proliferation to the same extent as rapamycin, without inducing cell apoptosis. After 6 days in coculture with feeder cells, all B cells showed CD27 memory B-cell phenotype. None of the immunosuppressive treatments modified the proportion between class-switched and non-class-switched memory B cells observed in nontreated cultures. The high predominance of CD27. Our results show that Tofa and STN can suppress B-cell antibody responses to an extent similar to rapamycin, in vitro; therefore these compounds may be a useful therapy against antibody-mediated rejection in transplantation.

Topics: Apoptosis; B-Lymphocytes; CD40 Ligand; Cell Proliferation; Cells, Cultured; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-2; Interleukins; Janus Kinase 3; Leukocytes, Mononuclear; Lymphocyte Activation; Piperidines; Protein Kinase C; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinazolines; Sirolimus

Data on how different immunosuppressive drugs affect cytomegalovirus (CMV)-specific T-cell responses may help guide more rational modification of immunosuppression in patients with CMV replication. We assessed the in vitro effects of individual standard and novel immunosuppressive drugs on a broad range of CMV-specific T-cell responses.. Peripheral blood mononuclear cells from healthy CMV-seropositive donors were preincubated with serial dilutions of tacrolimus, mycophenolate (MPA), sirolimus, tofacitinib, and belatacept. CMV-pp65 or CMV-pp72 peptide pools were used for stimulation. CMV-specific cytokine (Th1 and Th2) and chemokine responses were determined (a total of 5400 measurements). P<0.01 was set as significant.. After CMV stimulation, dose-dependent suppression of Th1, Th2, and chemokines was seen, but significant differences between drugs were present. For example, tacrolimus was more potent in inhibiting CMV-specific Th1 cytokines versus Th2, whereas MPA preferentially inhibited Th2 cytokines. In a comparison of the relative potency of each drug at different dosing ranges, tacrolimus had the strongest Th1 inhibitory effect (median inhibition of interferon-γ at 97.5%; P=0.004-0.008) followed by sirolimus (median inhibition at 82.4%). The remaining agents (MPA, belatacept, and tofacitinib) had less apparent dose-dependent effects on interferon-γ (belatacept median inhibition at 21.5%; P=0.004 vs. tacrolimus).. Immunosuppression-specific and dose-dependent reductions in CMV-specific cytokine release were observed with significant differences in Th1 versus Th2 profiles and in relative potency of the drugs.

Topics: Abatacept; Adult; Cytokines; Cytomegalovirus; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Humans; Immunoconjugates; Immunosuppressive Agents; In Vitro Techniques; Middle Aged; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Sirolimus; T-Lymphocytes; Tacrolimus; Th1 Cells; Th2 Cells; Transcriptome