L21- Immunotherapeutics Flashcards
(47 cards)
What is the aim of immunotherapy?
Prevent tissue damage and disruption of tissue function
Provide some examples of natural or synthetic small; molecule immunosuppressive drugs
- Powerful anti-inflammatory drugs of the corticosteroid family
- Cytotoxic drugs such as cyclophosphamide
- Noncytotoxic fungal and bacterial derivatives such as cyclosporin A, rapamycin
- Fingolimod (prevents effector lymphocytes from reaching periphery
What is a disadvantage of using immunosuppressive drugs?
Most of the drugs exert a broad inhibition of the immune system leaving it open to opportunistic pathogens
What immunosuppressive drug is used to inhibit proliferation of lymphocytes by interring with DNA synthesis and killing dividing cells?
Azathioprine
Cyclophosphamide
Mycophenolate
What does Cyclosporin A do?
Inhibit the calcineurin-dependent activation of NFAT;
Main target are T cell activation and proliferation but also act on B lymphocytes and granulocytes by blocking IL-2 production.
Which immunosuppressive drug inhibits proliferation of effector T cells by blocking Rictor-dependent mTOR activation?
Rapamycin (sirolimus)
Which immunosuppressive drug blocks lymphocytes trafficking out of lymphoid tissue by interfering with signalling by the sphinogosine-1-phosphate receptor?
Fingolimod (FTY270)
What do newer immunosuppressive drugs target?
Targeting specific aspects of the immune response.
Mostly via highly specific antibodies directed against specific proteins e.g. cytokines that cause tissue damage or excess inflammation
Where are corticosteroids?
Corticosteroids are a class of drug that suppresses the immune system and lowers inflammation in the body. Because corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like: asthma. arthritis.
Derivatives of the glucocorticoid family of steroid hormones.
What are the most common corticosteroid drug?
Prednison e, synthetic version of cortisol
In more detail, how do corticosteroids effect the immune system?
- Target anti-inflammatory function of monocytes and cytokine production by macrophages.
- Reduce CD4 T cell numbers
- Suppress expression of pro-inflammatory genes
- Inhibiting expression of adhesion molecules thereby inhibiting inflammatory cell migration
- Promote the apoptosis of leukocytes and lymphocytes
- Adverse effect multifaceted
What is a serious side effect of cytotoxic drugs such as azathioprine, cyclophosphamide, mycophenolate?
Because it is a immune suppression drug it kills all dividing cells and interferes with DNA synthesis.
This means that it also kills all dividing cells in tissues (skin, gut lining, bone marrow)
Are cyclosporine A, tacrolimus (FK506), rapamycin (sirolimus) toxic?
No. Non-toxic
Which immunosuppressive drug inhibits serine/threonine kinase mTOR?
Rapamycin
Which immunosuppressive drug inhibit calcineurin required for activation of NFAT (nuclear factor of activated T cells)
Cyclosporine A and FK506
What is Sphingosin 1 phosphate (S1P) and it’s role?
Although S1P is of importance in the entire human body, it is a major regulator of vascular and immune systems. In addition, it might be relevant in the skin. In the vascular system, S1P regulates angiogenesis, vascular stability, and permeability.
In the immune system, it is now recognized as a major regulator of trafficking of T- and B-cells. S1P interaction with its receptor S1PR1 is needed for the egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels. Inhibition of S1P receptors was shown to be critical for immunomodulation.
S1P has also been shown to directly suppress TLR mediated immune response from T cells and also inhibits migration of DCs
Fingolimod (FTY270) is an S1P analogue. T or F?
True
Which non-cytotoxic immunosuppressive drug Is widely used to treat transplant recipients?
Rapamycin as it interferes with T cell signalling
How do Rapamycin interfere with T cell signalling?
Like cyclosprin A and tacrolimus, rapamycin binds to intracellular proteins called immunophilins, forming complexes that interfere with the signaling pathways important for clonal expansion of lymphocytes
Which immune suppressive drug is a macrolide: (contains many-‐membered lactone ring to which is aPached one or more deoxysugars) and is derived from Streptomyces hygroscopicus, found on Rapa Nui?
Rapamycin
What immunosuppressive drug is used for transplant patients and in MS?
Fingolimod (FTY270)
Define in great detail the role of Fingolimod (FTY270)
- Antigen-‐specific stimulation of naïve T cells in lymph nodes generates CCR7‐effector memory T cells which recirculate to infected tissues and display effector function. CCR7+ central memory T cells are retained in lymph node to await antigenic restimulation.
- Egress from lymph nodes requires activation of the sphingosine 1-‐phosphate receptor 1 (S1P1 ), this overrides CCR7-mediated retention in lymph nodes. (Fingolimod binds to S1P 1 and causes aberrant internalization of the receptor this reduces responsiveness of T cells, with subsequent CCR7-‐mediated retention in lymph nodes – naïve and central memory T cells are retained)
What is the role of;
Depleting antibodies?
Eliminate lymphocytes in vivo by Fc receptor-‐mediated phagocytosis or ADCC (e.g. anti-lymphocyte globulin and alemutuzumab)
What is the role of;
Non-depleting antibodies?
Block function of target proteins
