Lecture 9 - pharmacology of immunosuppresants Flashcards
describe the immunology key players
- Antigen Presenting Cells (APCs): These cells include dendritic cells, macrophages, and activated B cells. They process and present antigens to T cells
- B cells and antibodies; natural antibodies and induced antibodies
- T cells: Different types of T cells: Helper T cells (CD4+): They assist other cells in the immune response.
Cytotoxic T cells (CD8+): They can kill infected cells and cancer cells.
Regulatory T cells (Treg): They modulate the immune response, preventing autoimmune diseases.
How does the immune system recognise alloantigens by direct presentation?
Recognition of non self antigens by direct presentation involves recognition of the intact MHC molecules by the self MHC molecules, presented by the Antigen presenting cells. involves CD4+ and CD8+ T cells.
How does the immune system recognise alloantigens by indirect presentation?
indirect presentation involves the donor MHC being processed by recipient APC. the processed fragemnts are then displayed by class II MHC presntation which cd4+ t cells recognise and respond to.
what are the roles of cytokines ?
IL – 2, IFN –Y, and TNF - B are important mediators of graft rejection.
IL – α promotes T-cell proliferation and generation of T – Lymphocytes.
IFN - Y is central to the development of DTH response.
TNF - B has direct cytotoxic effect on the cells of graft.
A number of cytokines promote graft rejection by inducing expression of class – I or class – II MHC molecule on graft cell.
The interferon (α, b and y), TNF – α and TNF - b all increases class – I MHC expression, and IFN - y increases class – II MHC expression as well.
what are different types of grafts and immune response in transplantation?
Autograft: Tissue transplanted from one site to another within the same individual.
Isograft: Tissue transplanted between genetically identical individuals.
Allograft: Tissue transplanted between genetically different members of the same species.
Xenograft: Tissue transplanted between different species.
The success of transplantation is largely dependent on the immune response of the recipient to the donor tissue
rejection types are Hyperacute: Immediate rejection.
Acute: Occurs shortly after the transplant.
Chronic: Long-term rejection.
what do immunosuppressant drug do?
Immunosuppressive drugs prevent graft rejection
anti- proliferatives;
inhibitors of T-cell activation;
anti-inflammatory agents; and
biologics, in particular antibodies
what is the impact of the impact of major histocompatibility complex (MHC) compatibility on the survival of grafts
Human leukocyte antigens (HLA) are genes in major histocompatibility complexes (MHC) that help code for proteins that differentiate between self and non-self.
MHC group of genes that code for proteins found on the surfaces of cells that help the immune system recognize foreign substances
Matching of major histocompatibility complex (MHC) alleles between the donor and recipient significantly improves renal allograft survival
what are the events following hyper acute rejection
Preformed Antibodies (Ab): These are antibodies that already exist in the recipient’s body against the donor antigens, such as blood group antigens.
Complement Activation: The preformed antibodies bind to the alloantigens on the transplanted tissue, activating the complement system.
Neutrophil Margination: Neutrophils adhere to the blood vessel walls.
Inflammation: The immune response leads to inflammation within the transplanted tissue.
Thrombosis Formation: The inflammatory process results in the formation of blood clots within the vessels of the transplanted organ.
what happens in acute rejection
Acute rejection is mediated by T-cells, macrophages, and antibodies (Ab).
It results in damage to myocytes (muscle cells) and endothelial cells (cells lining the blood vessels).
This process is characterized by inflammation within the transplanted organ or tissue
outline chronic rejection in organ transplantation
Occurrence within minutes to hours after host blood vessels are anastomosed to graft vessels
Chronic rejection is mediated by macrophages and T cells.
It is characterized by concentric medial hyperplasia, which refers to the thickening of the walls of blood vessels within the transplanted organ due to the proliferation of smooth muscle cells.
The condition also involves a chronic delayed-type hypersensitivity (DTH) reaction
what are the central events involved in transplant rejection
predominately effects the graft-host anastomosis which is similar in autoimmunity self antigens seen as non self
There is immune cell activation and cytokine or chemokine signalling. then, recruitment of additional immune cells to the site of the graft. pro-inflammation is caused which is the body’s immune response. cell growth, damage or scarring (fibrosis) can occur (usually in resposne to chronic rejection.)
what are pharmacological drugs used in preventing transplant rejection?
Glucocorticosteroids: prednisone*
IMPDH inhibitors: mycophenolate mofetil
Leflunomide: pyrimidinesynthesis inhibitor
Azathioprine
Calcineurin inhibitors: cyclosporine, tacrolimus
Mammalian target of rapamycin inhibitors:sirolimus (a.k.a rapamycin)
lymphocyte recirculation (S-1-P) inhibitors: FTY720 (Fingolimod)
what is tacrolimus use and moa?
Tacrolimus is used for liver, kidney, and heart transplants.
It serves as a second-line therapy for severe atopic dermatitis.
- TCR activation when T cell recognises antigen.
- Leads to activation of PCL and releases calcium ions
- the increase in calcium ions activates calcineurin
- Tacrolimus binds to FK binding protein and forms a complex which inhibits calcineurin
- inhibition prevents dephospho rylation of NFAT
- without dephosphoryaltion NFAT is not translocated to the nucleus
- This prevents NFAT from upregulating cytokines response, thus suppresses immune response.
what is mammalian target of rapamycin mTOR inhibitors?
Rapamycin/Sirolimus is initially identified as a macrolide antibiotic.
mTOR acts as a checkpoint by sensing cell status and regulates cell progress through the G1 to S phase.
sirolimus uncouples these regulatory activities, negatively affecting T cell proliferation and survival
it binds to FKBP12 foreign a complex that specifically inhibits mTOR. the drug inhibits IL-2 driven T cell proliferation and arrests the cell cycle in the G1 phase.
what is mycophenolate mofetil?
Mycophenolic acid is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn’s disease and lupus.
Mycophenolic acid from penicillium moulds
Inhibits synthesis of inosine monophosphate dehydrogenase (IMPDH); blocks purine synthesis, preventing proliferation of T and B cells
what is azathioprine?
Prodrug that releases 6-mercaptopurine
First immunosuppressive agent to achieve widespread use in organ transplant
azathiopurine interferes with DNA syntheiss and inhibits purien synthesis. it inhibits the prolferation of cells especially leukpocytes and prevents mitosis of proliferation of rapidly dividign cells such as activated b cells and t cells
what is azathiopurine prescribed for and its side effects?
Prescribed for
Renal transplantation: Experience with over 16,000
transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-
Rheumatoid Arthritis: treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms
Multiple Sclerosis, Crohn’s disease, myasthenia
gravis, chronic ulcerative colitis, and autoimmune hepatitis
Side effects
Leukopenia, bone marrow depression, macrocytosis, liver
toxicity (uncommon); blood-count monitoring required
what is fingolimod?
Fingolimod is used for multiple sclerosis and renal transplant patients.
It acts as an antagonist to sphingosine-1-phosphate (S1P) receptors on lymphocytes.
This antagonism enhances the homing of lymphocytes to lymphoid tissues and prevents their egress, leading to a reduction in the number of circulating lymphocytes (lymphopenia).
Fingolimod is not recommended for patients at known risk of cardiovascular events.
The drug is known to cause transient bradycardia (slow heart rate) and heart block after the first dose.
what are calcineurin inhibitors ?
Calcineurin inhibitors are a family of three drugs (cyclosporine, tacrolimus, and pimecrolimus) that suppress immune function
Tacrolimus and pimecrolimus are members of a class of topical immunomodulators.
they are Anti-inflammatory and Suppress T-lymphocyte responses.
Tacrolimus and pimecrolimus have similar mechanisms of action
used in ulcerative colitis refractory to corticosteroid treatment, rheumatoid arthritis, severe psoriasis
discusses novel pharmacological strategies in the context of immunoglobulins used for transplant patients
Biologic Induction Therapy: This is utilized in about 70% of new transplant patients. Biologic agents are used either to delay the use of calcineurin inhibitors, which have nephrotoxic potential, or to enhance the initial immunosuppressive therapy for patients at high risk of rejection.
Depleting Agents: These include lymphocyte immune globulin (ATGAM) and antithymocyte globulin (THYMOGLOBULIN). Their effectiveness comes from their ability to deplete CD3-positive T-cells at the time of transplantation and during antigen presentation.
Non-depleting antibodies and fusion proteins: This category includes:
Immune Modulators, such as anti-IL-2R monoclonal antibodies (mAbs), which block IL-2 mediated T-cell activation by binding to the IL-2 receptor, rather than depleting the T cells.
Abatacept (CTLA4-Ig), a fusion protein that modulates the immune response
what is muromonab CD3?
Reduces acute rejection in patients with organ transplants
It is a monoclonal antibody specifically targeted at the CD3 receptor, which is a membrane protein located on the surface of T cells.
The drug works by binding to the CD3 glycoprotein on the T cell surface.
It leads to the destruction of CD3-positive T cells through several mechanisms: Fc mediated apoptosis, antibody-mediated cytotoxicity, and complement-dependent cytotoxicity.
what his antithymocyte globulin
TG contains antibodies that are specific to a variety of T cell antigens, including CD2, CD3, CD4, CD8, CD11a, and CD18.
TG works by reducing the concentration of T cells in the body through complement-dependent cytolysis and cell mediated opsonisation.
Leading to T cell clearance from the circulation by the reticuloendothelial system
Antithymocyte globulin-equine (Atgam®),
Antithymocyte globulin-rabbit (RATG, Thymoglobulin®)
what is abatacept CRLA4-Ig fusion protein?
Trade Name: The medication is known commercially as Orencia.
Disease Target: It is indicated for the management of Rheumatoid Arthritis, a chronic inflammatory disorder affecting joints.
Abatacept works by dampening the activation of T cells. It inhibits the costimulatory pathway involving the proteins CD80/86 and CD28. This pathway is essential for the full activation of T cells
