Immunosuppressive drugs

Immunosuppressive

drugs

RJM ten Berge Afd. Inw. Geneeskunde AMC

contents

 

Immunosuppressive drugs

 

overview

 

targets

 

mechanism of action

 

Effects on immune capacity

 

measured by responses to vaccination

Immunosuppressive drugs

 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

Immunosuppressive drugs

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

Immunosuppressive drugs

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

Nat Immunol 8:26,2007

Am J Transplantation 8:1972, 2008

B-lymphocytes as target for immunosuppression

Immunosuppressive drugs

mechanism of action

Inhibition of:

 

Cell activation

 

Cytokine synthesis and signal transduction

 

Nucleotide - en DNA - synthesis

 

Cell migration

Immunosuppressive drugs

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

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

Immunosuppressive drugs

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

J Clin Invest 120:1036-9,2010 Complement inhibitors Proteasome inhibitors CD28/B7 blockade anti-CD40 BAFF- inhibitors anti-CD20 rituximab ocrelizumab ofatumumab belimumab atacicept bortezomib eculizumab abatacept belatacept

Immunosuppressive drugs

inhibitors of cell migration

 Corticosteroïds  Chemokine (receptor) inhibitors  anti-CXCR2  anti-CXCR3 Nat Immunol 9:988, 2008 Transplantation 87:360, 2009

Immunosuppressive drugs

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

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)

* Meningococcen sepsis type W135

Meningococcal sepsis complicating eculizumab treatment despite prior vaccination

What about immune responsiveness

during treatment with

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

Tetanus toxoid PPS Immunocyanine P/CsA P/MP A P/everolimus HC ratio IgG P/CsA P/MP A P/everolimus HC P/CsA P/MP A P/everolimus HC

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

new immunosuppressive drugs

kinase inhibitors: JAK-3 inhibitors

Nat Immunol 10:356,2009

tasocitinib

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