Immunosuppressive drugs

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Neal Butler
7 years ago
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1 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

2 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

3 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

4 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: ,2004 Two signal concept of T cell activation Pathways of co-stimulation 4

5 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: ,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: ,2004 B cell and antibody related biologicals eculizumab Complement inhibitors bortezomib J Clin Invest 120:1036-9,2010 5

6 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

7 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

8 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):

9 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

10 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,

Treatment of Rheumatoid Arthritis in the New Millennium. Neal I. Shparago, D.O., FACP, FACR

Treatment of Rheumatoid Arthritis in the New Millennium Neal I. Shparago, D.O., FACP, FACR What is RA? Symmetric inflammatory polyarthritis Rheumatoid factor positive in 80% Anti-CCP positive in approximately