Drug That Alter The Immune System Flashcards
Immune suppressants: MOA
Reduce the activation or efficacy of the immune system to treat—autoimmune
diseases OR lower the body’s ability to reject an organ transplant
Autoimmune disease is:
when the person’s immune system mistakenly identifies the person’s native tissues as foreign and initiates a destructive
response against them
How do immune suppressants affect organ transplant patients?
drugs selectively inhibit rejection of the transplanted tissues and prevent the patient from immune compromise while
prolonging the life of the transplanted
organ
Principle approach to immune therapy?
to alter the lymphocyte function with drugs or antibodies against immune proteins
3 parts of Immune activation:
• Part One—T cells trigger at the CD3 receptor complex by an antigen on the surface of an antigen presenting cell [APC]
• Part Two—costimulation—where CD80 and CD86 on the surface of the APC engage CD28 on T cells, this activates many pathways, including the Ca++ Calcineurin pathway; this activation triggers the production of IL-2; IL-2 the binds to IL-2 receptor [CD25] on the surface of T cells
• Part Three—activation of the cell cycle via the mammalian target of rapamycin [mTOR] and leading to T cell proliferations
Antithymocyte Globulins
Atgam
-Polyclonal antibodies produced by isolating gamma globulin fractions of serum obtained from rabbits or horses after immunization with human thymocytes
-These agents deplete circulating T cells and apoptosis of activated T cells
-Rabbit preparations are preferred because of great potency and less toxicity
Used at time of transplant to prevent early rejection [along with other anti-rejection drugs]
• Can also be used in severe rejection or steroid resistant acute rejection
• Used for 3-10 days to cause profound lymphopenia [that can last >1 year]
• Given IV infusion— ½ life is 3-9 days
• Patient is premedicated with steroids, APAP, and anti-histamine to reduce
infusion-related reactions
• Prolonged use associated with profound immunosuppression
Basiliximab
Simulect is trade name drug
• Chimeric murine/human MAB that binds to the alpha-chain of the IL-2 receptor [CD25] on activated T cells—interfering with proliferation of these cells
• Blocking this receptor inhibits the ability of any antigenic stimulus to activate T-cell response system
• Approved for preventing acute rejection in kidney transplant in combination with CYA and steroids
Basiliximab
Using this drug may allow for lower doses or delayed use of calcineurin inhibitors
• Can be helpful in those with delayed graft function and can reduce risk of calcineurin inhibitor-associated renal toxicity
• This drug is NOT T cell depleting and is mainly used in induction—as opposed to treating rejection
• Given by IV infusion
• ½ life is 7 days
• Drug is well tolerated
Alemtuzumab
• Campath is the trade name drug in the family
• Humanized MAB that binds to CD52 on both T and B cells, causing depletion of both lymphoid cell lines
• Depletion of T and B cells begins soon after infusion—recovery of these cells is gradual—T cells recover in 6-12 months; B cells recover in 6 months
• Approved to treat CLL, but used in transplant induction and antirejection for acute cellular and antibody-mediated rejection
• Because of its potent and prolonged
immunosuppressive effects—when using Campath, it is recommended to initiate or continue prophylaxis
for Pneumocystis pneumonia and HSV
• Removed from US market in 2012, so that it could be relabeled for use in MS—so this drug has to be obtained through the Campath Distribution Program
if it is to be used in transplant immunomodulation
• Lemtrada is the name of this drug when
prescribed for MS
Rituximab
• Rituxin is trade name in the family
• Chimeric MAB against the antigen CD20 on pre-B cell, mature B cells and memory B cells
• This drug causes B-cell depletion by causing B-cell death and blocking B-cell activation and maturation to antibody-forming plasma cells
• Already grown up plasma cells do not express CD20 antigens, and are unaffected by Rituxin
• Approved for B-cell lymphoma, post-transplant lymphoproliferative disease [PTLD; lymphoma after transplant] and RA
• Use in transplant is for antibody removal, which as been used in ABO incompatibility transplants, desensitization protocols and treatment of AMR [acute antibody-mediated rejection]
• IV infusion causes rapid and sustained depletion of B lymphocytes, with the B cell count returning to normal in 9-12 months
• Has a BB warning for reactivation of JC virus [John Cunningham virus that causes progressive multifocal leukoencephalopathy [PML] in the [immunosuppressed] and Hepatitis B virus
Bortezomib
• Velcade is the trade name drug in the family
• Acute antibody mediated rejection involves production of high levels of antibodies by plasma cells, either newly made B cells or those that existed before transplant.
• This novel agents is a proteasome inhibitor that causes cell cycle arrest and apoptosis of normal plasma cells—thus decreasing
antibody production
• Velcade is approved to treat multiple myeloma, but has been adapted to treat AMR
• Given IVP or SQ injection
• Metabolized by CYP 450 enzymes
• Hepatic dysfunction care occur—but it is rare
Intravenous Immunoglobulin [IV Ig]
• IV Ig contains immune globulins prepared by human plasma pooled form many donors
• Often used in autoimmune disease—pretransplant desensitization regimens and treating AMR
• Immune modulation effects on T and B cells occur at high doses; low doses are used to prevent infection by replacing immunoglobulins removed during plasmapheresis
• MOA is not well understood—high doses appear to cause B-cell apoptosis and modulate B-cell signaling
• Inhibits binding of antibodies to the transplanted organ and activation of complement
• ½ life of the drug is 3-4 weeks
• ADEs—headache, fever, chills, myalgias, hypo or
hypertension [can be moderated by slowing the infusion]
• Serious ADEs—rare, but can include aseptic
meningitis, acute renal failure and thrombotic events
What are maintenance immunosuppressant drugs?
• Maintenance immune modulators are intended to maintain enough immunosuppression to prevent
organ rejection while minimizing risk of infection, malignancy and ADEs
• These drugs can be divided into
• Calcineurin inhibitors—CYA and Tacrolimus
• Costimuation blockers—Belatacept
• mTOR inducers—Sirolimus and Everolimus
• Antiproliferatives—Mycophenolate and Azathioprine
Calcineurin Inhibitors
• Cyclosporin—Neoral; Sandimmune [prototype]
• Tacrolimus—Prograf; Astagraf XL; Envarsus XR
• These drugs block signal transduction through the Ca++ calcineurin
path
• Calcineurin—a Ca++ dependent protein phosphatase, dephosphorylates nuclear factor of activated T cells [NFAT]—allowing
NFAT to enter the T-cell nucleus and bind to DNA, leading to transcription and production of cytokines, including IL-2
• CYA binds to cyclophilin, where Tacrolimus binds a protein called FK-binding protein [FKBP]
• These drug-protein complexes inhibit the activity of Calcineurin—preventing T-cell activation
• Tacrolimus is preferred [over CYA] due to its decreased rate of allograft rejection
• Tacrolimus is approved to prevent renal, liver and cardiac organ transplant—but it is the workhorse to prevent all solid organ
transplants
• CYP 450 enzymes 3A4, 3A5 and p-glycoprotein expressed in liver and
GI tract re responsible for variability in oral absorption and metabolism of CYA and Tacrolimus
• Dosing is based on 12° trough level; goal trough levels vary between different organs and transplant center protocols
• One major drawbacks of these meds is renal toxicity—which has led to combination with other immune suppressants
• Infections are possible
• Patients on these agents are given prophylactic medications posttransplant
• Other ADEs—hirsutism [common in CYA]
Costimulation Blockers
• Belatacept [Nulojix]
• 2nd generation drug that is a recombinant fusion protein of CTLA-4— which binds to CD80 and CD 86 on antigen presenting cells [APCs]
• Binding of this agent to CD80 and CD86 prevents CD28 from binding to those molecules and thus inhibits signal 2 of the T-cell activation pathway
• Approved for renal transplant, in combination with Basiliximab,
Mycophenolate mofetil and steroids
• Can be a substitute for Calcineurin inhibitors to avoid long-term
nephrotoxic, CV and metabolic complications
• Belatacept is the 1st IV maintenance drug—it is dosed in two phases
• Initially—given 4 times in the 1st month at a higher dose to build up drug levels and then decreased to once a month dosing
• After 4 months—the dose is also decreased
• Monthly dosing may be helpful in those for whom compliance is an issue
• Clearance of Belatacept is not affected by age, sex, race, renal or hepatic function
• This drug increases the risk of PTLD—particularly of the CNS
• Contraindicates in those who are seronegative for EBV—a common cause of PTLD
• EBV titers are drawn before a decision to prescribe this drug is made
1st generation costimulation blocker—Abatacept [Orencia] is approved
for RA
