Pb&t Pharmacology Of Immunosuppression

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Alloimmunity (definition)
What can it cause?

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a condition in which the body gains immunity, from another individual of the same species, against its own cells.
Graft versus host disease (GVHD)

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The result of complement activateion by antibody binding to endothelial cells of the transplanted organ, resulting in thrombosis and ischemia.

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Hyperacute rejection

Matching can be done prior, so drug therapy for hyperacute rejection is often unecessary.

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2 components of acute rejection:

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Cellular and humoral

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Believed to be both humoral and cellular in nature, does not occur until months or years after transplantation.

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Chronic Rejection

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Acute Cellular Rejection
Mediate by?
Commonly seen when?
Preventative measures?

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Acute Cellular Rejection
Mediate by cytotoxic T cells which causes interstitial and vascular damage.
Commonly seen in the initial months after transplantation.
Preventative measures: Immunosuppression of T cells.

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Acute Humoral Rejection
Mediate by?
Commonly seen when?
Preventative measures?

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Acute Humoral Rejection
Mediate by B cells that produce antibodies directed against endothelial cells (acute vascular rejection)
Commonly seen 7-10 days post-op
Preventative measures: Immunosuppression

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Most common life-threatening pathology associated with organ transplantaion.

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Chronic rejection

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Chronic rejection is thought ot result from

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chronic inflammation caused by the response of activated T cells to donor antigen.

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Activated T cells release cytokines that recruit ____________ into the graft. This leads to:
Treatment:

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Macrophages
Scarring of graft tissue and organ failure.
None at this time.

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Graft versus leukemia effect

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Beneficial mild-to-moderate GVHD when donor immune cells attach recipient tumor cells that have survived the aggressive chemo and radiation.

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Central Tolerance

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the specific clonal deletion of autoreactive T and B cells during thier development from precursor cells in the thymus and bone marrow.

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Deletion of autoreactive T cells by Fas-Fas ligand mediated apoptosis, activation of T suppressor cells, or induction of T cell anergy due to antigen presentationin the absence of costimulation.

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Peripheral tolerance

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Genetic factors, in that the presenc eof certian MCH subtypes may predispose T cells to

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loss of self-tolerance, and possibly autoimmunity

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Define molecular mimicry:
(can lead to a breakdown of tolerance)

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Epitopes from infectious agents are similar to self antigens to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides.

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List the 8 mechanistic approaches to pharmacologic suppressionof the immune system

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1. Inhibit gene expression
2. Depletion of clonally expanding lymphocyte populations
3. Inhibition of intracellular signaling
4. Neutralize cytokines to prevent T-cell stimulation
5. Deletion of specific immune cells w/ Ab
6. Inhibition of costimulation by APC's
7. Block cell adhesion to prevent migration and homing of inflammatory cells
8. Inhibit innate immunity

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Glucocorticoids

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steroid hormones that exert thier physiologic actions by binding to the cytosolic glucocorticoid receptor.

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After binding, where does the glucocorticoid-glucocorticoid complex tranlocate to, and bind? Effect?

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The nucleus and binds to GRE's in the promoter region of specific genes, either up-regulating or down-regulating gene expression.

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Down regulate expression of many inflammatory mediators including key cytokines susch as TNF and IL1 & 4.

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glucocorticoid

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Overall effect is anti inflammatory and immunosuppressive, and is therefore used to treat rheumatoid arthritis and transplant rejection.

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glucocorticoids

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What are typical adverse effects of glucocorticoids?

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Diabetes, reduced resistance to infection, osteoporosis, cataracts, increased appetite leading to weight gain, HTN, masking of inflammation.

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Can you terminate glucocorticoid therapy abruptly? Why?

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No, abrupt cessation of glucocorticoid therapy can result in acute adrenal insufficiency (weeks are needed to reestablish ACTH production by the hypothalamus and pituitary)

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Two classes of cytotoxic agents used as immunosuppresents?

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Antimetabolites
Alkylating agents

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______ structural analogues of natural metabolites that inhibit essential pathways involving these metabolites.

________ interfere with DNA replication and gene expression by conjugating alkyl groups to DNA.

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Antimetabolites
Alkylating agents

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Leflunomide & Mycophenolate mofetil.

Azathioprine & Methotrexate

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Newer antimetabolites that have fewer adverse effects and may be used therapeutically at lower doses.

Older antimetabolites with more adverse reactions.

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Azathiprine
Type of drug:
Reacts with:
Used for:

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Type of drug: prodrug of the purine analogue 6-MP
Reacts with: sulfahydryl compounds such as glutathione
Used for: Prevent graft rejection and infl bowel disease

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Methotrexate
Type of drug:
Effects:
Used for:

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Type of drug: Folate analogue
Effects: Cytotoxic & antiinflammatory
Used for: RhArthritis, psoriasis, and GVHD prevention

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Antimetabolite that has been shown to cause apoptosis of activated CD4 and CD8 T cells, but not resting cells. A versitile drug due to its antineutrophil, anti-T cell and antihumoral effects.

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Methotrexate
(and 5-fluorouracil, 6-mercaptopurine andmycophenolic acid)

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Mycophenolic acid (MPA) is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the formation of _______

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guanosine

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Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection.

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Mycophenolic acid (MPA)

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Common adverse drug reactions (≥1% of patients) associated with mycophenolate therapy include diarrhea, nausea, vomiting, infections, leukopenia, and/or anemia. Mycophenolate sodium is also commonly associated with fatigue, headache, and/or cough

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Mycophenolic acid (MPA)

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an immunosuppressant drug used to prevent rejection in organ transplantation. It was initially marketed as the prodrug mycophenolate mofetil (MMF) to improve oral bioavailability.

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Mycophenolic acid (MPA)

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Used for immunosuppression to prevent rejection in organ transplantation, RhArth, myasthenia gravis, psoriasis, hemolytic anemia, and inflammatory bowel disease.

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Mycophenolic acid (MPA)

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An inhibitor of pyrimidine synthesis, specifically blocking the synthesis of UMP.

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Leflunomide

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Leflunomide has been shown to be most effective in reducing ________ populations, but a significant effect on _______ has also been observed. Adverse effects are:

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B-cells

T-cells

Diarrhea and reversible alopecia (hair loss)

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Toxic drug that alkyllates DNA. Use is limited to disorders of humoral immunity, especially lupus. Can cause bladder CA due to acrolein

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Cyclophosphamide(cy)

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A cytokine that acts in an autocrine and parcrine mode to cause activation and proliferation of T cells

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IL2

By inhibiting calcineuring mediate NFAT dephosphorylation, CyA prevents translocation of NFAT to the nucleus and thereby suppresses IL2 production.

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Cyclosporine (CsA)is a specific inhibitor of T-cell mediated immunity which enabled widespread, whole organ transplant. Its adverse effect are:

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Nephrotoxicity, HTN, hyperlipidemia, neurotoxicity, and hepatotoxicity.

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Nephrotoxic like CsA, but 50-100x more potent. Also inhibits calcineurin, inhibiting___ ___ ___ ____, but doesn't suppress B cells or NK cells.

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Tacrolimus
IL3 IL4 IFN-y TNFa

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This, when complexed with FKBP does not inhibit calcineuin, instead it blocks the IL2 receptor signaling required for Tcell proliferation by inhibiting mTOR

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Serolimus (rapamycin)

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Why is serolimus (rapamycin) sometimes a better choice than CsA or Tacrolimus?

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It does not cause nephrotoxicity

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Etanercept, infliximab and adalimumab are all ___ __________ used to treat

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TNF inhibitors
arthritis, crohn's disease, ulcerative collitis and psoriasis

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_________ is a recombinant form of IL-1receptor antagonist used to treat RhArthritis. It has modest effects on pain and swelling but decreases osteoclast production. May cause neutropenia and increased risk of infection

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ANAKINRA

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ATG (anti thymocyte globulin (resulting in broad immunosuppresion) therapy is often complicated by ______ _______ _______ which results form activation of T cells and relase of T cell cytokines before the antibody coated T cells can be cleared by macrophages

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Cytokine release syndrome

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an immunosuppressant drug given to reduce acute rejection in transplant patients. A major milestone in the prevention of acute allograft rejection was achieved with the development of the mAb ____, the first mAb to be approved for clinical use in humans. It is a murine monoclonal IgG2a antibody that reacts with the T cell receptor-CD3 complex on the surface of circulating human T cells

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OKT3

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Second line agent when CsA or glucocorticoids fail.

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OKT3

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Rituximab

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partially humanized anti CD20 antibody. Causes profound deleteion of B cells

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Daclizumab and basiliximab

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Ab against CD25, the high affinity IL-2 receptor, thus limiting Tcell activation

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Campath-1 (CD25) is an antigen expressed on most mature lymphocytes.
Alemtuzumab (anti-CD25) causes

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causes prolonged and sustained depletion of lymphocytes.

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LFA-3 (CD58) is the counter receptor for CD2, an antigen expressed at high levels on the surface of memory effector T cells.
Alefacept (a fusion protein that interrupts CD2-LFA3 signaling) is contraindicated in:

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Patients with HIV bc it CD4 and CD8 Tcell pops

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Prevents delivery of costimulatory signal btwn APC and T cell

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Abatacept

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A monoclonal antibody against LFA1, disrupts LFA1-ICAM1 interactions thereby limiting Tcell adhesion, activation, and migration to sites of inflammation.

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Efalizumab

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Natalizumab (used to treat MS)

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Monoclonal antibody against a4 integrin that inhibits immune cell interactions with cells expressing VCAM1 or MAdCAM-1

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Membrane attack complex

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typically formed on the surface of intruding pathogenic bacterial cells as a result of the activation of the complement system, and it is one of the ultimate weapons of the immune system, causing cell lysis;is initiated when the complement protein, C5 convertase, cleaves C5 into C5a and C5b

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Eculizumab

(possible treatment for Paroxymal nocturnal hemoglobinuria and macular degeneration)

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humanized monoclonal ab against C5, a complement protein that mediates late steps in complement activation.

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Humoral Immune Response

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is the aspect of immunity that is mediated by secreted antibodies (as opposed to cell-mediated immunity which involves T lymphocytes) produced in the cells of the B lymphocyte lineage (B cell). Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction. Humoral immunity is called as such, because it involves substances found in the humours, or body fluids.