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Immunosuppression

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24 views19 pages

Immunosuppression

Uploaded by

shulamiteyeboah
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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Newman Osafo, BPharm, PhD.

Department of Pharmacology, FPPS, CoHS, KNUST


[email protected]
§ The immune system evolved to discriminate self from non-
self.

§ Innate immunity (natural immunity) is primitive, does not


require priming, and is of relatively low affinity, but it is
broadly reactive.
§ The major effectors are complement, granulocytes,
monocytes/macrophages, NK cells, mast cells, and basophils.

§ Adaptive immunity (learned immunity) is antigen specific,


depends on antigen exposure or priming, and can be of
very high affinity.
§ The major effectors are B and T lymphocytes.

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§ These cells not only are important in the normal immune
response to infection and tumors but also mediate
transplant rejection and autoimmunity.

§ Immunoglobulins (antibodies) on the B-lymphocyte


surface are receptors for a large variety of specific
structural conformations.

§ T lymphocytes recognize antigens as peptide fragments


in the context of self MHC antigens (called HLAs in
humans) on the surface of APCs

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§ Once activated by specific antigen recognition, both B
and T lymphocytes are triggered to differentiate and
divide.

§ This leads to release of soluble mediators (cytokines,


lymphokines) that perform as effectors and regulators of
the immune response.

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§ “Graft-versus-host disease” results from the immunological
rejection of a transplanted tissue by the recipient’s immune
system.

§ The intensity of rejection is minimized with increased


compatibility between donor and recipient.

§ Classical immunosuppressive therapy employs


glucocorticoids, Calcineurin inhibitors,
Antiproliferative/antimetabolic agents and Biologicals
(antibodies).
5
cyclophilin

Steroids

T-cell activation and sites of immunosuppressive action. 6


Adapted from: Goodman and Gilman
§ Induction therapy with biological agents is used to
delay the use of the nephrotoxic calcineurin inhibitors or

§ To intensify the initial immunosuppressive therapy in


patients at high risk of rejection

§ Biological agents for induction can be divided into two


groups: the depleting agents and the immune
modulators

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§ Depleting agents consist of lymphocyte immune
globulin, ATG, and muromonab-CD3 mAb.

§ Their efficacy derives from their ability to deplete the


recipient’s CD3-positive cells at the time of
transplantation and antigen presentation.

§ Immune modulators, i.e. the anti–IL-2R mAbs, do not


deplete T lymphocytes, but rather block IL-2–mediated
T-cell activation by binding to the α chain of IL-2R
(CD25)

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§ Have broad anti-inflammatory effects on multiple
components of cellular immunity

§ Glucocorticoids also curtail activation of NF-κB

§ Inhibit T cells from making IL-2, proliferating and inhibit


the activation of cytotoxic T lymphocytes.

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§ The most effective immunosuppressive drugs in routine use
are the calcineurin inhibitors cyclosporine and tacrolimus
§ MOA
Target intracellular signaling pathways induced as a consequence of T
cell receptor activation
§ Tacrolimus mediated blockade of calcineurin-catalyzed
dephosphorylation blocks expression of cytokine genes,
including IL-2

§A nephrotoxic and neurotoxic agent. GI complaints;


hypertension; hyperkalemia; hyperglycemia are also
possible.

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§ Sirolimus (Rapamycin) inhibits T-lymphocyte activation and
proliferation downstream of the IL-2 and other T-cell growth
factor receptors

§ A newer indication for sirolimus is the avoidance of calcineurin


inhibitors, even when patients are stable, to protect kidney
function

§ Everolimus is approved for treatment of astrocytoma, breast


cancer, kidney and liver transplant rejection prophylaxis,
pancreatic neuroendocrine tumor, renal angiomyolipoma, and
renal cell cancer.

§ It is chemically closely related to sirolimus but has distinct


pharmacokinetics. 11
§ Mycophenolate mofetil is a prodrug that is rapidly hydrolyzed
to the active drug Mycophenolic acid

§ A selective, noncompetitive, reversible inhibitor of inosine


monophosphate dehydrogenase (IMPDH) in T and B cells, an
enzyme in the de novo pathway of guanine nucleotide
synthesis. This inhibits their proliferation.

§ GI and haematologic toxicities: leukopenia, pure red cell


aplasia, diarrhea, and vomiting; are common

§ Others: Azathioprine, Fingolimod

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§ Multiple costimulatory and inhibitory molecules interact to
regulate T-cell responses.

§ Immune activation requires two signals that emanate from


the interaction of membrane proteins on APCs and T cells

§A growing number of antibodies directed at these


interacting proteins permits interruption of immune
activation to produce a state of immune suppression

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§ CD3is a component of the TCR complex on the surface of
human T lymphocytes.

§ Antibodies
directed at the ε chain of CD3 have been used with
considerable efficacy in human transplantation.

§ Theanti-CD3 antibody is monoclonal and targets the CD3 chain


of the TCR, inducing its endocytosis and T-cell inactivation and
removal through phagocytosis.

§ Muromonab-CD3 (OKT3), is no longer marketed due to its side


effects: It frequently causes cytokine release syndrome and
severe pulmonary edema. 14
§ Induction of specific immune responses by T lymphocytes
requires two signals: an antigen-specific signal via the TCR
and a co-stimulatory signal provided by the interaction of
molecules such as CD28 on CD4 lymphocyte with CD80 and
CD86 on APCs

§ Belatacept is a selective T-cell co-stimulation blocker that


potently binds the cell surface costimulatory ligands (CD80
and CD86) present on APCs. Other: Abatacept

§ An increased risk of posttransplant lymphoproliferative


disorder in Epstein-Barr virus seronegative patients has been
observed
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§ The anti-CD25 mAbs bind with high affinity to the α
subunit of the IL-2 receptor and act as a receptor
antagonist, inhibiting T-cell activation and proliferation
without inducing cell lysis

§ Daclizumab is a humanized murine complementarity-


determining region/human IgG1 chimeric mAb.
Basiliximab is a murine-human chimeric mAb.

§ They are relatively safe as induction agents, with most of


the clinical trials reporting adverse reactions rates
comparable to placebo
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§ TNF-alpha is a pro-inflammatory cytokine that has been implicated
in the pathogenesis of several immune-mediated intestinal, skin, and
joint diseases.

§ Infliximab is a chimeric IgG1 mAb with high affinity to TNF-α and


prevents the cytokine from binding to its receptors.

§ Etanercept is a fusion protein that targets TNF-α.

§ Adalimumab is another anti-TNF product for intravenous use. This


recombinant human IgG1 mAb is approved for use in rheumatoid
arthritis, ankylosing spondylitis, Crohn disease, juvenile idiopathic
arthritis, plaque psoriasis, psoriatic arthritis, and ulcerative colitis.
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§ Alemtuzumab binds the CD52 protein that is wildly
expressed on B cells and T-cells, as well as
macrophages, NK cells, and some granulocytes.

§ Alemtuzumab binding to CD52 induces an antibody-


dependent lysis of cells and a profound leukopenia that
may last for more than a year.

§ Neutropenia remains the most common adverse effect

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§ T-cell–mediated acute rejection has been become much less of a
problem, while B-cell–mediated responses such as antibody-mediated
rejection and other effects of donor-specific antibodies have become
more evident.

§ Bothbiologicals and small molecules with B-cell–specific effects now are


in development for transplantation

§ These include humanized mAbs to CD20 and inhibitors of the two B-cell–
activation factors, BLYS (B lymphocyte stimulator) and APRIL (a
proliferation-inducing ligand), and their respective receptors.

§ TheCD20 antibodies rituximab and ocrelizumab deplete circulating


mature B lymphocytes
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