PPOM 1 Week 18 LEC 158-168 WORK IN PROGRESS

(158) cell-mediated arm of the immune response

involves the ingestion and digestion of antigen by antigen-presenting cells such as macrophages

(158) IL-2

Cytokine secreted by Activated TH cells, causes proliferation and activation of cytotoxic T lymphocytes as well as TH1 and TH2 cell subsets

(158) Humoral Response

Triggered when B lymphocytes bind antigen via their surface immunoglobulin

(158) Immunosuppressive therapies

Drugs that suppress the immune system; are important in preventing rejection of allografts and in the treatment of disorders due to immune system dysregulation, such as autoimmune and inflammatory diseases

(158) Acute rejection

results from expression of HLA class I and II antigens in the allograft and early infiltration of CD8+ T cells

(158) Function of CD4+ T cells with Acute Rejection

orchestrate acute rejection by recruiting the effector cells that damage the graft, including CD8+ T cells macrophages, natural killer cells, and B cells

(158) Maintenance immunosuppression therapy

Initiated following transplantation to prevent acute rejection – typically the combination of a calcineurin inhibitor, an antimetabolite, and a glucocorticoid

(158) Antithymocyte globulin (ATG)

polyclonal antibodies prepared by immunization of horse, sheep, or rabbits with human thymocytes; contains antibodies to a wide variety of T cell antigens including MHC antigens and produces profound lymphopenia

(158) Function of Antithymocyte globulin (ATG)

used as induction therapy to prevent early allograft rejection and to treat severe glucocorticoid-resistant acute rejection episodes, along with other immunosuppressants

(158) Mechanism of Action of Antithymocyte globulin (ATG)

Purified polyclonal antibodies may bind a variety of T cell surface antigens, leading to depletion of peripheral T cells that circulate between the blood and lymph

(158) Therapeutic Effects of Antithymocyte globulin (ATG)

Profound T cell depletion; Preferred agent for patients with high and low risk of acute rejection

(158) Adverse Effects of Antithymocyte globulin (ATG)

can cause infusion reactions characterized by flu-like symptoms and pain and erythema at the infusion site; Rapid infusion may lead to cytokine release syndrome. Prolonged administration may lead to profound immunosuppression, opportunistic infections, post-transplant lymphoproliferative disorder (PTLD). People of reproductive age should use effective contraception during and at least 3 months following treatment

(158) Basiliximab

monoclonal antibody directed against IL-2 receptor α chain (CD25) expressed on activated T cells, thus prevents T cell proliferation and cytokine production. It does not cause T cell depletion

(158) Therapeutic Uses of Basiliximab

Non-depleting agent administered for induction therapy in transplant patients at low risk of rejection, along with IV methylprednisolone and maintenance immunosuppressive combination therapy

(158) Alemtuzumab

anti-CD52 monoclonal antibody infrequently used in transplant induction therapy

(158) CD52

cell surface glycoprotein expressed on T and B cells

(158) Mechanism of Action of Alemtuzumab

binds CD52 on T and B cells; causes depletion of T and B cells by complement-mediated and Direct antibody-dependent lysis of T and B cells.

(158) Therapeutic Effects of Alemtuzumab

Potent and prolonged panlymphocyte (T and B cells) depletion, reduces host immune response against the transplanted organ; profound, prolonged immunosuppression. An infrequently used alternative

(158) Adverse Effects of Alemtuzumab

can cause serious, even fatal, pancytopenia, infusion reactions, infections, and autoimmune reactions. For patients who could become pregnant, effective contraception is recommended during and at least 3 months after the last dose

(158) Glucocorticoids

Immunosuppressive drugs that are included in both induction and maintenance immunosuppressive regimens

(158) Therapeutic Effects of Glucocorticoids

Prevention and treatment of transplant rejection; rapidly reduce T cell populations by lysis or redistribution, with suppressive effects on inflammatory cytokines and chemokines. Concentrations of neutrophils, monocytes, basophils, and eosinophils are also decreased

(158) Allograft rejection

Recipient’s immune system attacks foreign antigens in the allograft

(158) Graft-versus-host disease (GVHD)

Immunologically competent immune cells in allograft transplanted into immunodeficient recipient recognize the recipient’s antigens as “foreign” and attack it. Common complication of allogeneic hematopoietic stem cell transplant. Can occur following transplantation of solid organs rich in lymphoid cells, such as liver, or with transfusion of unradiated blood.

(158) Hyperacute rejection

within minutes to hours of the transplant, Cannot be stopped by immunosuppressant drugs

(158) Acute rejection

days to weeks; Cellular, humoral or both. Results from expression of HLA class I and II antigens in the allograft and early infiltration of CD8+ T cells

(158) Function of CD4+ T cells

orchestrate acute rejection by recruiting the effector cells that damage the graft, including CD8+ T cells macrophages, natural killer cells, and B cells

(158) Adverse Effects of Acute Rejection

associated with a high incidence of complications, such as infection and graft vs host disease

(158) Chronic rejection

most often progresses gradually over several years, Leads to fibrosis and loss of graft function

(158) Examples of Calcineurin inhibitors (CNIs)

Tacrolimus, Cyclosporine

(158) Examples of Antimetabolites

Mycophenolate mofetil, Azathioprine

(158) Examples of Glucocorticoids

Methylprednisolone, Prednisone

(158) Examples of T cell costimulatory blockers

Belatacept (CTLA-4 fusion protein)

(158) (159) Examples of Proliferation signal/mTOR inhibitors

Sirolimus

(158) Mechanism of Action of Calcineurin inhibitors (CNIs)

Immunophylin-CNI-calcineurin complex prevents activation of NFAT; Decreases synthesis of IL-2 and other cytokines

(158) Mechanism of Action of Antimetabolites

Inhibit de novo purine (nucleic acid) synthesis, which inhibits DNA synthesis in T and B cells

(158) Mechanism of Action of Glucocorticoids

Induce lipocortin → inhibits PLA2 → inhibits synthesis of prostaglandins and lipoxygenase products. Inhibit T cell proliferation. Humoral immunity dampened. . Rapidly reduces T cell populations by lysis or redistribution, which has suppressive effects on inflammatory cytokines and chemokines

(158) Mechanism of Action of Belatacept

CTLA-4 binds CD80/86 on antigen presenting cells, which prevents the costimulatory T cell activating signal: the binding of CD28 on T cells to CD80/86

(158) (159) Mechanism of Action of Sirolimus

Blocking the protein kinase mTOR interrupts progression from the G1 to S phase, causing cell cycle arrest, thus inhibiting cytokine mediated T cell proliferation.

(158) Post-transplant lymphoproliferative disorders (PTLD)

B lymphocyte proliferations that occur in patients receiving chronic immunosuppression (due to decreased T cell immune surveillance) for solid organ or allogeneic hematopoietic cell transplantation

(158) Mechanism of Action of Basiliximab

high affinity binding to IL-2Rα on surface of activated T cells; competitively blocks IL-2 binding to activated T cells, prevents T cell activation. IL-2R downregulation prevents proliferation

(158) Adverse Effects of Basiliximab

Hypersensitivity reactions, Generally well tolerated

(158) Acute Effects of Glucocorticoids

Impaired immunity, increased risk of opportunistic infections, Delayed wound healing

(158) Delayed Effects of Glucocorticoids

Peptic ulcers; GI bleeding, Cushingoid effects, Moon face; ruddy complexion; Nuchal fat deposition (buffalo hump); Weight gain; abdominal obesity

(158) Maintenance therapy

Gradually taper down each agent in the initial triple therapy over several weeks to months to a maintenance level for prevention of rejection

(159) Maintenance immunosuppressant regimens

combinations of two to four drugs with different mechanisms of action

(159) initial maintenance regimen for most patients

calcineurin inhibitor, an antimetabolite, and a glucocorticoid – most frequently tacrolimus, mycophenolate mofetil, and prednisone

(159) Examples of calcineurin inhibitors (CNIs)

cyclosporine, tacrolimus

(159) Examples of antimetabolites

mycophenolate mofetil (MMF), azathioprine (AZA)

(159) Mechanism of Action of calcineurin inhibitors (CNIs)

form a ternary immunophilin-CNI-calcineurin complex within the cytosol, which prevents dephosphorylation and activation of cytosolic NFAT

(159) Mechanism of Action of antimetabolites

interfere with de novo purine synthesis resulting in inhibition of T cell and B cell proliferation

(159) mTOR

cytoplasmic protein kinase, which interrupts DNA and protein synthesis

(159) Mycophenolate

potent reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase which blocks the synthesis of guanine monophosphate

(159) cytosolic NFAT

a transcription factor critical in regulating gene transcription and production of cytokines and T cell receptor-mediated signaling

(159) Calcineurin

calmodulin-dependent serine/threonine protein phosphatase

(159) _____ binds to cyclophilin.

Cyclosporine

(159) _____ binds FK binding protein (FKBP).

Tacrolimus

(159) _____ is generally preferred by many transplant centers. It is associated with lower acute rejection rates and is better tolerated than cyclosporine.

Tacrolimus

(159) _____ is preferred because of superior efficacy and better side effect profile.

mycophenolate mofetil (MMF)

(159) _____ is converted to 6-mercaptopurine and then to the thioinosine monophosphate and 6-thioguanine toxic nucleotides which are incorporated during DNA synthesis.

azathioprine (AZA)

(159) Adverse Effects of calcineurin inhibitors (CNIs)

nephrotoxicity, hypertension, hyperlipidemia, hyperglycemia, hyperkalemia, and neurotoxicity

(159) Adverse Effects of mTOR inhibitors

bone marrow suppression (anemia, leukopenia, thrombocytopenia), dyslipidemia, poor wound healing (antiangiogenic effect), hepatotoxicity, pneumonitis, and increased post-transplant mortality, in addition to nausea, vomiting, and diarrhea or constipation; contraindicated in pregnancy

(159) Adverse Effects of mycophenolate mofetil (MMF)

bone marrow suppression, mainly neutropenia, nausea, abdominal cramping, and persistent diarrhea; teratogenic

(159) Adverse Effects of azathioprine (AZA)

(most common) bone marrow suppression manifested by leukopenia. Other side effects, which are seen mainly at higher doses, include nausea, diarrhea, and hepatotoxicity (very high doses).

(159) Adverse Effects of Belatacept

associated with increased risk of EBV-associated post-transplant lymphoproliferative disorder (PTLD); risk is higher in EBV seronegative patients. Common side effects include edema, hypertension, headache, diarrhea, constipation, anemia, and cough. Contraindicated in EBV seronegative patients. Use for liver transplant patients is not recommended due to an increased risk of graft loss and death. Limited info on use during pregnancy.

(159) Administration of calcineurin inhibitors (CNIs)

taken orally once daily (IV formulations are available); substrates of CYP3A4 and P-glycoprotein. High potential for drug interactions

(159) Administration of mycophenolate mofetil (MMF)

oral drug (IV available) twice daily; hydrolyzed in the liver to active mycophenolic acid, which is excreted in urine as glucuronide metabolites

(159) Administration of azathioprine (AZA)

oral drug, once daily dosing. 6-MP is inactivated by xanthine oxidase and thiopurine methyltransferase

(159) Administration of Belatacept

given IV every 4 weeks (maintenance phase) in combination with oral mycophenolate mofetil (MMF) and a glucocorticoid

(159) Administration of mTOR inhibitors

taken orally twice daily; substrates of CYP3A4 and P-glycoprotein

(159) Belatacept

Drug that is a selective T cell costimulation blocker. It is a recombinant fusion protein of CTLA-4

(159) Mechanism of Action of Belatacept

induces immunosuppression by preventing the costimulatory T cell activating signal – binding of CD28 on T cells to CD80/86.

(159) Therapeutic Uses of Belatacept

alternative to a calcineurin inhibitor (CNI) for prevention of acute allograft rejection in EBV seropositive patients with biopsy-proven CNI nephrotoxicity

(159) Strong Inducers of CYP3A4 and P-glycoprotein

Carbamazepine, Rifampin, Phenobarbital, Phenytoin, St. John’s wort

(159) Strong Inhibitors of CYP3A4 and P-glycoprotein

Ritonavir and other protease inhibitors, Cobicastat, Itraconazole and other azole antifungals, Clarithromycin, Grapefruit juice

(159) When taking _____, Patients deficient in TPMT are at risk for severe life-threatening myelosuppression.

azathioprine (AZA)

(159) Effect of targeting Genes

Inhibit gene expression of pro-inflammatory mediators

(159) Effect of targeting Lymphocytes

Deplete lymphocyte populations and other specific immune cells

(159) Effect of targeting/inhibiting Lymphocyte signaling

block activation and expansion of lymphocytes

(159) Effect of targeting/inhibiting Cytokine signaling

Neutralize cytokines and cytokine receptors essential for mediating the immune response

(159) Effect of targeting/blocking Costimulation

induce anergy

(159) Effect of targeting/blocking Cell adhesion

prevent migration and homing of inflammatory cells

(159) Effect of targeting/inhibiting Innate immunity

Inhibit complement activation

(159) Drugs that target Genes

Glucocorticoids, Antimetabolites, Alkylating agents

(159) Drugs that target Lymphocytes

Polyclonal antibodies; Anti-CD3; Anti-CD20; Anti-CD25; Anti-CD52; Alemtuzumab

(159) Effect of target/inhibit Lymphocyte signaling

Cyclosporine, Tacrolimus, Sirolimus, Everolimus

(159) Drugs that target/inhibit Cytokine signaling

Anti-IL-2Rα, Anti-TNFα agents, JAK inhibitors

(159) Drugs that target/block Costimulation

Abatacept, Belatacept

(159) Drugs that target/block Cell adhesion

Natalizumab, Ustekinumbab, Vedolizumab

(159) Drugs that target/inhibit Innate immunity

Eculizumab

(160) Intrinsic pathway of coagulation

activated by damage inside vasculature. Platelets, exposed/damaged endothelium, sube ndothelial collagen, and other chemicals can activate this arm of pathway. Slower but thought to generate a more robust coagulation response

(160) Extrinsic pathway of coagulation

activated by trauma that causes blood to leave vasculature. Tissue thromblastin factor is activated and sets off cascade. Quicker pathway

(160) Function of Tissue plasminogen activator

converts plasminogen to plasmin

(160) Function of Plasmin

cleaves fibrin and serum fibrinogen, destroys coagulation factors, and blocks platelet aggregation

(160) Function of Alpha-2-antiplasmin

inactivates plasmin

(160) Prothrombin time (PT)

time to clot (seconds), mainly measure of extrinsic pathway (factor VII)

(160) International normalizing ratio (INR)

used to normalize Prothrombin time (PT) and compare International normalizing ratio (INR) between different institutions (which have different labs). Calculation based on results of Prothrombin time (PT), used to monitor patients being treated with warfarin (anticoagulant)

(160) (164) Activated partial thromboplastin time (aPTT or just PTT)

time to clot (seconds),for monitoring UFH and direct thrombin inhibitor therapy, measure of intrinsic pathway

(160) Thrombin time (TT)

time to clot, dependent on thrombin catalyzing fibrin production - not really used

(160) Bleeding time (BT)

time it takes for a patient to stop bleeding, looks for platelet dysfunction - not really used; all platelet disorders have increased bleeding time