Pharm - Immunomodulating Compounds - Handout

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Administration of nonspecific immunoglobulins derived from pooled plasma of adults provides

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passive immunity

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Administration of nonspecific immunoglobulins derived from pooled plasma of adults provides specific protein or peptide constituent of an organism

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active immunity

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what cell is central in the rejection of grafts

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T cells

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when does hyperacute graft rejection occur... talk about ti



mediate by what?

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rejection of solid organ allograft occurs usually within the first few hours post-transplantation because vascularization is rapidly destroyed. It is humorally mediated; preformed host antibodies against alloantigens bind to antigen on the trans-planted organ. The antigen-antibody complexes activate the complement system, causing massive thrombosis in the capillaries, which prevents the vascularization of the graft. The kidney is most susceptible to hyperacute rejection; the liver is relatively resistant, possi-bly because of its dual blood supply, but more likely because of incompletely understood immunologic properties.

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talk about acute rejection

mediate by what?

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occurs usually within the first few days to months after transplantation. It is mediated by monocytes and both CD8+ cytotoxic lymphocytes and Th1 CD4+ lym-phocytes. Small populations of B lymphocytes, NK cells, neutrophils, and eosinophils all contribute to rejection through secretion of inflammatory cytokines

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talk about chronic rejection

mediate by what?

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is characterized by insidious loss of function of the grafted organ. It seems to be due to both immunologic and nonimmunologic processes. The hallmarks are arteriopathy (vascular endothelial injury) and fibrosis. Blood vessel walls thicken and be-come blocked. Low-grade cell-mediated responses or deposition of antibody-antigen complexes damage the blood vessel lining and trigger inappropriate repair responses. The vessel lumen can be obliterated from proliferation of smooth muscle cells migrating from the vessel wall and increased production and deposition of matrix proteins. Parenchymal damage and interstitial fibrosis of the transplanted organ can also occur.

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is a common complication of allogeneic bone mar-row transplantation in which functional immune cells in the transplanted marrow recog-nize the recipient as “foreign” and mount an immunologic attack. It can also take place in a blood transfusion under certain circumstances. Glucocorticoids are the standard of care for the treatment of acute and chronic disease

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GVHD

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is a rela-tively uncommon complication of both solid organ and al-logeneic bone marrow transplantation.

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Posttransplant lymphoproliferative disease (PTLD)

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purified sterile gamma globulin obtained from the serum of horses immunized with human thymus lymphocytes

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ATGAM

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purified sterile gamma globulin obtained from the serum of rabbits im-munized with human thymocytes

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Thymoglobulin:

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PK OF POLYCLONAL ANTIBODIES

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Poor distribution to lymphoid tissue; bind to circulating lym-phocytes, granulocytes, platelets, bone marrow cells; plasma t½ 1.5-12 days (ATGAM), 2-3 days (Thymoglobulin); lymphopenia may persist >1 year

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MOA OF POLYCLONAL ANTIBODIES

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The antibodies deplete circulating lymphocytes by direct cytotoxicity (both complement and cell mediated) and block lymphocyte function by binding to cell surface molecules involved in the regulation of cell function

Antithymocyte globulin contains cytotoxic antibodies that bind to proteins on the surface of human T lymphocytes such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, and HLA class I and II molecules on the surface of human T lymphocytes

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EFFECTS OF POLYCLONAL ANTIBODIES

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Destruction or inactivation of T cells impairs delayed hypersensitivity and cellular immunity, which results in marked suppression of cellular immunity to the tissue graft

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CLINICAL USE OF POLYCLONAL ANTIBODIES

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INDUCTION THERAPY
PREVENTION OR TX OF GVHD
ACUTE REJECTION OF RENAL TRANSPLANT (WITH OTHER IMMUNOSUPPRESSANTS)
OTHERS: APLASTIC ANEMIA TX OF MYELODYSPLASTIC SYNDROME
RENAL TRANSPLANT WITH DELAYED GRAFT FUNCTION (ANTITHYMOCYTE GLOBULIN GIVEN EARLY TO AVOID OTHER TOXIC THERAPIES)

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which is most commonly used depleting agent

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antithymocyte globulin (thymoglobulin)

other two are rarely used due to poorer efficacy and acute side effects of muromonab

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pt presents with fever, chills, leukopenia, thrombocytopenia, and headache
xenogeneic proteins - humoral immunity intact (injection of ATG and ALG can elicit major side effects - premedicate with corticosteroids, acetoaminophen and an antihistamine and admin of antiserum by SLOW infusion into big vein)
pt also has serum sickness and glomerulonephritis (rash, itching, arthralgia, fever, lymphadenopathy, hypotension, shock, enlarged spleen, proteinuria)

also infections and possible malignancy
what did he take?

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one fo the polyclonal antibodies - thymoglobulin or lymph immune globulin

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PK lasts 7 days after therapy is done

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muromonab CD-3

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MOA of muromonab

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binds to epsilon chain of cd3 ;

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what is muromonab used for

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acute organ transplant rejection (it reverese acute renal, hepatic, cardiac, kidney/pancreas transplant rejection episodes that are resistant to conventional tx (high dose steroids or antithymocyte globulin)

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a pt presents with high fever, chills, rigors, heac, tremor, N/V/D, abdominal pain, malaisem myalgias, arthralgias, generalized weakness 30 minutes after he took this medication

whats going on here

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cytokine release syndrome
a life-threatening massive release of cytokines; the major adverse effect of anti-CD3 therapy (TNF-alpha is the major cause of hte toxicity)

you must pretreat these pt's and concurrent infusion with diphenhydramine, methylprednisolone and acetominophen

less common complaints: skin, cardioresp and neuropsych rxns and aseptic meningitis

other symptoms: anaphylactoid/hypersensitivity rxn (these usually happen in first 10 minutes rather than first 30 minutes) ; HAMA rxn (human anti mouse antibodies)

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when is muromonab contraindicated

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in pt's with mouse antibody titers > 1:1000

and also in pt's predisposed to seizures

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Humanized murine chimeric antibody (90% human; 10% mouse)

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Daclizumab:

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Chimeric mouse-human

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Basiliximab:

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this drug lasts 20 days in serum
can have saturation of IL-2Ralpha on circulating lymphs for 120 days afte transplant
its given immediately preoperatively and every 2 weks for the total of 5 doses

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daclizumab

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this drug last in serum for 7 days
receptor blockade of 25-35 days
administered immediately preoperatively and on days 0 and 4

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basiliximab

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this group of drugs competitively blocks the alpha chain of the IL2 receptor which is expressed on the surface of ACTIVATED T cells --> downreg of IL2 receptor and comp antag of IL2 induced T cell activation and proliferation

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dacliz and basil

depletion of T cells is NOT a part of the MOA

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why use basil and dacliz

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both used as induction therapy in renal transplant pt's in combination with calcineurin and corticosteroids

basil (OFF LABEL) --> tx of refractory actue GVHD and to prevent liver or cardiac transplant rejection

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you subscribe your transplant pt this drug and tell him he's at risk for:
anaphylactoid / hypersens rxns (within 24 hours)
HAMA rxn (possible)
opportunistic infection and lymphoproliferative disorders are possible (incr. with add'l immunosuppression)

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basil and dacliz (less HAMA with dacliz)

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this type of drug induces the antiinflammatory protein, lipocortin which inhibits the enzyme phospholipase A2 which inhibits synthesis of prostaglandins and lipoxygenase products

it inhibits cell-mediated immunity by inhibiting the proliferation of T lymphocytes and are cytotoxic to certain subsets of T cells

humoral immunity is also dampened (but little effect)

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glucocorticoids

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what are the effects of glucocorticoids

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broad antiinflammatory effects
Lymphocyte apoptosis by curtailing NF-κB activation Lymphocyte redistribution Downregulation of proinflammatory IL-1 and IL-6 ↓ Synthesis of IL-2 → inhibition of T lymphocyte proliferation ↓ Cytotoxic T lymphocyte activation ↓ Chemotaxis and ↓ lysosomal enzyme release of neutrophils and monocytes

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you have a pt scheduled for a transplant and you are going to use a drug as prophylaxis. you tell him that there are short and long term adverse effects such as:
short
impaired immunity
delayed wound healing
hyperglycemia, diabetes
incr. plasma cholesterol
incr. salt retention and incr. BP
mood - euphoria/depression
longterm
peptic ulcers ; GI bleeding
moon face, ruddy complexion
cataracts
nuchal fat deposition (buffalo hump)
weight gain, abd obesity
muscle wasting/weakness
osteoporosis and avascular necrosis of bone

what drug is it

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glucocorticoids

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what to remember about the PK of the calcineurin inhibitors tacrolimus and cyclosporine

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large variability in blood levels and clearance rates
high and low fat means decrease AUC
CYP3a4 metabolism in lumen
cross placenta highly protein bound cross placenta and distributed to milk
must reduce dose in pts with hepatic dysfunction (no change in pt's with renal or dialysis pt's) and blood level monitoring is REQUIRED to ensure therapeutic dose ; large potential for drug interactions (CYP and PgP drugs)

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talk about function of calcineurin and what the calcineurin inhibitors do

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NORMAL
T cell activation --> incr. cytoplasmic calcium --> stims calcineurin-catalyzed dephosphoryolation of NFAT --> NFAT to nucleus --> incr. gene transcription of key cytokines, such as IL2,3,4, TNF, IFN --> inflam response and growth and differentiation of T lymphs

cyclo binds with cyclophilin nad calcineurin and inhibits the phosphatase activity of calcineurin and then NFAT never translocates to nucleus

tacrolimus does the same thing but its binds to FKBP-12 complex and calcineurin first

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you have a pt who is about to receive a kidney transplant
and you give him a prophylaxis tx, but you warn him that there are MANY risks of adverse effects with this drug such as:
renal dysfunction, HTN (50% of transplant pt's and ALL cardiac transplant pt's) and neurotoxicity (tremor, HA, motor disturbances, seizure)
nephrotoxicity (common in all pt's)
GI (NVD)
and when you combine this drug with corticosteroid --> INCR. risk of DM

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calcineurin inhibitors

cyclos - hyperuricemia, hyperlipidemia, gingival hyperplasia, hirsutism
tacrolimus - hyperkalemia, hyperglycemia, diarrhea, alopecia (no uric acid or LDL cholesterol)

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this drug is extensively taken up by RBCs (95%)
widely distributedi n tissue
maintenance dose reduction req'd in pt's with hepatic dysfunction (CYP3a4 and PgP)
it inhibits T cel lactivation downstream of IL2 and other GFs ; it binds to FKBP-12 and then to mTOR --> Cell cycle arrest

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sirolimus

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you hv a pt that has acute GVHD from an allogeneic stem cell transplantation and you give him a med to help treat it, but you warn him that this is an "off label" use for this particular medication

the label calls for hte med to be used as a prophylactic organ transplant rejection med with a calcineurin med and a GC ; it can also be used topically for some dermatological disorders or in the use of soft tissue carcinoma
NOT FOR USE IN LIVER TRANSPLANTS OR LUNG

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sirlimus

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after a transplant you tell your pt that he needs a medication that will help prevent GVHD but the side effects are hypertricleridemia (can be controlled by diet), heptatoxicity, myelosuppression (thrombocytopenia, leukopenia, anemia), delayed wound healing (can be bad after surgery), fluid accumulation and other GI (NVD) and acne

it also have HIGH drug interactions (CYP3a4 and pgp drugs

what med?

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mTOR inhibitor
sirolimus

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this drug has a short half life compared to other drugs in its class ; it is removed by methylation in the liver and or erythrocytes

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antimetabolites

azathioprin ; 6-MP

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you have a crohn's patient with ALL and you want to give him a med that helps with both

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6-MP (antimetabolite - mycophenolate mofetil)

its sister drug azathioprine can be used for crohn's and severe rh arth

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you have a pt with severe rheumatoid arthritis and you want to give him something to help with flare ups

you warn him that this medication can cause bone marrow suppression (thrombocytopenia, leukopenia, anemia), skin rashes, fever, NVD and it can be hepatotoxic

also, he cannot take allopurinol with this drug bc it blocks xanthine oxidase (enhances toxicity of 6-MP)

what drug

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azathioprine (largerly replaced by mycophenolate mofetil)

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this drug inhibits the de novo synthesis of purines (inhibits T and B cell proliferation) ; it traps lymphocytes in earl G1 phase --> apoptosis

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MPA mycophenolate mofetil

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you give your pt prophylaxis tx of transplant rejection with a glucocorticoid and a calcineurin inhibitor

you tell him this drug is sometimes used in pt's with severe psoriasis, profilerative lupus nephritis, myasthenia gravis and in the prevention and tx of GVHD

you warn him that he may develop a leukopenia, pure red cell aplasia, D/V and he will be at an increased risk for infection (especially for JC virus -> progressive multifocal leukoencephalopathy and BK virus --> nephropathy
he also must watch out for lymphoproliferative disorders

he also cannot take antacids or cholestyramine resins will decr. absorption (which is otherwise high)
PREGNANT WOMEN CANNOT TAKE THIS

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MPA mycophenolate mofetil

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Murine = muro…mab

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mouse origin

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Chimeric = …iximab

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murine constant region domains replaced with human domains

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Humanized = …xumab or …zumab

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rebuilding of the monoclonal antibody using se-quences derived from human antibodies while retaining complementarity-determining regions

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Human = …mumab

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use of transgenic mice to produce the antibodies or constructed us-ing cDNA libraries