Immunosuppressive drugs RJM ten Berge Afd. Inw. Geneeskunde AMC contents overview targets mechanism of action Effects on immune capacity measured by responses to vaccination Immune response 1
calcineurin inhibitors cyclosporin, tacrolimus mtor inhibitors sirolimus, everolimus anti-metabolites azathioprine, mycophenolate alkylating agents cyclophosphamide corticosteroids prednisolone JAK-STAT inhibitors tasocitinib cell depleting agents alemtuzumab, ATG inhibitors of cell migration CK receptor antagonists co-stimulation blockers belatacept proteasome inhibitors bortezomib monoclonal antibodies monoclonal antibodies Alemtuzumab CD52 on all mononuclear cells; depleting Basiliximab CD25 on activated T cells; nondepleting Rituximab CD20 on B cells; depleting Eculizumab C5a; blocks formation of membrane attack complex Infliximab, Adalimumab TNFα targets calcineurin inhibitors calcineurin mtor inhibitors mtorc1,mtorc2 anti-metabolites purines,pyrimidins alkylating agents DNA corticosteroids innate IR, cell migration JAK-STAT inhibitors JAK-STAT signaling cell depleting agents membrane molecules inhibitors of cell migration chemokine receptors co-stimulation blockers co-stimulatory molecules proteasome inhibitors proteasome monoclonal antibodies cell surface molecules 2
T-lymphocytes as target for immunosuppression Nat Immunol 8:26,2007 B-lymphocytes as target for immunosuppression Am J Transplantation 8:1972, 2008 mechanism of action Inhibition of: Cell activation Cytokine synthesis and signal transduction Nucleotide - en DNA - synthesis Cell migration Non-specific inflammation 3
depletion; inhibition of cell activation anti-t cell antibodies ATG OKT3 (anti-cd3) anti-b cell antibodies rituximab pan-lymphocyte mab alemtuzumab (anti-cd52) costimulatory blockade belatacept (CTLA4-Ig) N Engl J Med 351:2715-2729,2004 Two signal concept of T cell activation Pathways of co-stimulation 4
inhibition of cytokine synthesis and cytokine signal transduction Calcineurin inhibitors cyclosporine tacrolimus CD25 mab basiliximab mtor inhibitors (target of rapamycin) sirolimus everolimus N Engl J Med 351:2715-2729,2004 inhibition of nucleotide- and DNA- synthesis anti-proliferative drugs azathioprine MMF (mycofenolate mofetil) MPA (mycophenolic acid) alkylating drugs cyclophosphamide N Engl J Med 351:2715-2729,2004 B cell and antibody related biologicals eculizumab Complement inhibitors bortezomib J Clin Invest 120:1036-9,2010 5
inhibitors of cell migration Corticosteroïds Chemokine (receptor) inhibitors anti-cxcr2 anti-cxcr3 Nat Immunol 9:988, 2008 Transplantation 87:360, 2009 inhibitors of non-specific inflammation Corticosteroids Inhibitors of C'-activation C5a mab (eculizumab) TNFα-inhibitors etanercept (fusion protein) infliximab, adalimumab (mab-anti-tnfα) IL1R-antagonist anakinra Immunosuppressive drug therapy limitations lifelong not antigen-specific no tolerance (opportunistic) infections secondary malignancies cardiovascular risk specific adverse effects 6
Casus Meningococcal sepsis complicating eculizumab treatment despite prior vaccination 19-year old woman factor H mutation, ahus, renal transplantation in february 2008 Immunosuppression: basiliximab, prednisolone, MMF and tacrolimus To prevent recurrence of HUS: plasma exchange (PE) January 2009: allergic reactions to plasma constituents Start eculizumab two-weekly Beforehand: vaccination with tetravalent meningococcal polysaccharide vaccine Mencevax (ACYW135) April 2010: meningococcal sepsis caused by serotype W135 18; successfully treated with penicillin second vaccination with Mencevax third vaccination with the tetravalent meningococcal conjugate vaccine Menactra (ACYW135) Meningococcal sepsis complicating eculizumab treatment despite prior vaccination * Meningococcen sepsis type W135 What about immune responsiveness during treatment with immunosuppressive drugs? 7
Immune response after vaccination in renal transplant patients 36 patients 1 jaar after renal transplantation prednisolone (P) plus cyclosporine A (CsA) prednisolone (P) plus mycophenolic acid (MPA) prednisolone (P) plus everolimus 13 healthy control individuals Vaccinations Immucothel (immunocyanine) prim T-cell dependent immune response (IR) Tetanus toxoid sec T-cell dependent IR Pneumovax 23 sec T-cell independent IR H Struijk, F Bemelman 2009 Study design Day 0: blood withdrawal and vaccination Day 14: blood withdrawal Humoral response IgG antibody levels Cellular response IFN-γ, IL-4, IL-2, IL17 Elispot H Struijk, F Bemelman 2009 Treatment with predn/mycophenolate inhibits responses to vaccination Immunocyanine Tetanus toxoid PPS ratio IgG P/CsA P/MPA P/everolimus HC P/CsA P/MPA P/everolimus HC P/CsA P/MPA P/everolimus HC Struijk et al, Kidney Int 78(9):934-40. 2010 8
Immune responses in vivo effect of immunosuppressive drugs humoral cellular primary second primary second corticosteroids = = azathioprine = =?? cyclofosfamide = cyclosporine = = Prednisolone/cyclosporine = = Prednisolone/mycophenolate Prednisolone/everolimus = = CONCLUSION Vaccination ineffective during treatment with: mycophenolate cyclophosphamide rituximab (Lvd Kolk et al Blood 100:2257, 2002) Vaccination unaffected/slightly diminished during treatment with: azathioprin, cyclosporin, everolimus infliximab, adalumimab (Rheum45:106,2006; Curr Op Rheum20:295,2008) 9
new immunosuppressive drugs kinase inhibitors: JAK-3 inhibitors Nat Immunol 10:356,2009 Inhibitors of C'-activation C5a inhibitors C5a receptor inhibitor C5a mab (eculizumab) J Am Soc Nephrol 19: 2302, 2008 Am J Transplantation 9: 231, 2009 10