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INTRODUCTION In order to provide a detailed analysis of recent pharmacological developments involving the human immune system, it is firstly necessary to introduce the innate and adaptive immune responses. Immunosuppressants and immuno modulators will be differentiated between and a selection of new and often experimental drugs belonging to each category will be provided. Specific drugs will be described including the pharmacokinetics and pharmacodynamic's involved with each type. The possible clinical uses will be alluded to along with details from recent research. INNATE IMMUNITY Innate immunity is the first line of defence and comprises physical (skin), biochemical (complement, lysozyme) and cellular (macrophages, neutrophils) mechanisms (Katzung, 1998). All these mechanisms are non-specific, anti-microbial agents which work in conjunction with adaptive immune responses to provide a more effective system (Downie et.
al. , 1995). ADAPTIVE IMMUNITY The adaptive immune system is split into two mechanisms: humoral immunity and cell-mediated immunity. A basic understanding of these concepts is necessary for the purpose of understanding the specific effects of different immuno pharmacological agents. HUMORAL IMMUNITY Humoral or antibody-mediated immunity is associated with B-lymphocyte cells.
Antigens are foreign molecules that initiate an immune response, they have inherent immunogenicity (Tortora & Grabowski, 1996). Upon contact with an antigen, B-cells divide to produce a clone of plasma cells capable of the production of antibodies. Antibodies are immunoglobulins, modified blood proteins with a specific action against antigens. Five main sub-types of immunoglobulins have been identified of which IgG is the most abundant in bodily fluids (Hopkins, 1995). Several cells are known to initiate the process of plasma cell differentiation and are known collectively as antigen presenting cells (APCs) (Waller & Renwick, 1994). Lymphokines The antigen on the surface of the APC triggers TH-cells to produce hormone-like lympho kines (Lesson, 1993).
Lymphokines are cytokines, regulators of the immune reactions which are produced by lymphocytes. Examples of these chemicals include interleukin's, interferon and tumour necrosis factors. Their action involves the regulation of the proliferation, differentiation and activity of leukocytes (Dale et. al. , 1994). The nature of lymphocyte stimulation will determine which class of immunoglobulin will be produced (Waller & Renwick, 1994). The role of complement & antibody-antigen complexes Antibodies have two distinct functions: to recognise and combine with an antigen, and to activate a defence mechanism for example by activating the complement sequence (Dale et.
al. , 1994). This sequence involves more than thirty proteins (Mollnes & Harbor, 1996) and has the function of the destruction and removal of invading micro-organisms and subcellular debris and to promote clearance of antigen-antibody complexes (Dale et. al. , 1994). These functions are achieved mainly via complements ability to attract leukocytes (Lesson, 1993). The interaction of antibody with specific antigen results in the formation of the antibody-antigen complex. This complex has several functions: for instance, to immobiliser an antigen therefore preventing attack upon host cells, to block active toxic regions of particular bacteria, and to allow phagocytic attack.
Memory cells Once the antigens have been destroyed the plasma cells disappear leaving a few as memory cells which enable a swift response upon second exposure to the antigen (Trounce, 1997). Memory cells are the basis of active immunisation against bacteria (Downie et. al. , 1994). Humoral immunity is most efficient against antigens dissolved in body fluids, that is extracellular pathogens, primarily bacteria whereas cell-mediated immunity is most effective against intracellular pathogens such as viruses (Tortora & Grabowski, 1996).
CELL-MEDIATED IMMUNITY Cell-mediated immunity is mainly concerned with T-lymphocytes. It is this form of immunity that is thought to be responsible for tissue transplantation rejection (Tortora & Grabowski, 1996). T-cells possess receptors upon their surface which recognise antigens, these receptors are similar to the antibodies released by B-cells. Upon contact with an antigen, T-cells produce memory and effector cells as do the B-cells. However, T-cells produce a variety of effector cells (Downie et.
Al. , 1995). TC-cells & TH-cells The cells produced are mainly Cytotoxic cells (TC-Cells or CD 8 +) or Helper cells (TH-cells, or CD 4 +). TC-cells recognise and destroy virally infected host cells, hence they are also known as killer-cells (Trounce, 1997). It is also thought that cancerous cells can be destroyed by the same mechanism (Dale et. al. , 1994).
TH-cells release lympho kines which activate local macrophages (Waller & Renwick, 1994). Meaning big eaters macrophages engulf micro-organisms and secrete lysosomal enzymes, complement components and some lympho kines (Dale et, al. , 1994). IMMUNOSUPPRESSION & IMMUNOMODULATION By providing an overview of the adaptive immune responses it becomes apparent that two areas of pharmacological enquiry are of interest: immunosuppression and immuno modulation. The former concept involves developing agents that suppress the immune responses. This area is important in the treatment of organ and tissue transplant rejection and also the treatment for certain diseases resulting from immune system irregularities. The latter area involves agents that augment or alter certain components of the immune system and are therefore important in cancer and AIDS management (Katzung, 1998).
NEW IMMUNOSUPPRESSANTS The prototype immunosuppressant, cyclosporine was discovered in the 1970 s Almost three decades later there is much investigation into the development of novel more effective immunosuppressive drugs (Dale et. al. , 1994). Traditionally immunosuppressants have been shown to be important in prolonging the life of transplanted organs. However, purely by their nature they greatly weaken the patients defence mechanism and therefore increase the risk of infection by opportunistic pathogens (Downie et. al. , 1995).
Traditional thinking advocates these drugs in the treatment of autoimmune diseases where the immune system produces antibodies against various self tissues (Trounce, 1997). However, new approaches (to be discussed later) prefer the use of immuno modulators to treat these disorders. Unfortunately many immunosuppressants are non-specific and lead to therapeutic inconsistencies that produce a wide range of pharmacokinetic and pharmacodynamic variations between different individuals (Kahan, 1999). Thus the latest drugs are being developed with more specificity in mind. A selection of these new drugs including mycophenolate mofette, thalidomide, sirolimus and 15 -deoxyspregualin, will be provided and their mechanisms of action, when understood, described. Mycophenolate mofette Mycophenolate Mofetil (MM) is a newly developed immunosuppressant which has been proven to be promising in the management of organ transplantation.
Introduced in 1997, MM has been mainly utilised in kidney transplantation treatments in conjunction with cyclosporine and corticosteroids (Hoffman & Jones-Reeder, 1998). When used in the combination described, MM has substantially reduced the incidence of kidney rejection within the first six months following transplantation (Nutley, 1995). This new drug has also been the subject of studies involving liver transplantation where it proved to reduce the incidence of rejection when combined with tacrolimus and steroids without increasing the risk of secondary infections (Jain et. al. , 1997). In comparative trials with azathioprine, MM has proved to be more selective and effectively decreases episodes of rejection in renal transplant patients (Barron, 1996). In animal studies MM has been used successfully for heart and pancreatic cell transplantation but further trials are needed to prove efficacy before use on human patients. (Saltiel, 1994).
Other recent studies involve the use of MM to treat autoimmune diseases such as rheumatoid arthritis (Dureza et. al. , 1999). Isolated from the mould penicillium glaucus (Katzung, 1998), MM, brand name cell cept, has greatly improved the ratio of immunosuppressive activity versus side effects (Hoffman & Jones-Reeder, 1998). Administered orally, MM is hydrolyzed to the active metabolite mycophenolic acid in the liver and gastro-intestinal tract and excreted by the kidney in urine. (Barron, 1996). By inhibiting nucleic acid synthesis via only the de nova pathway, MM can selectively inhibit T and B-cell activity (Saltiel, 1994). The result of this action leads to the prevention of T and B-cell proliferation, the inhibition of antibody formation, and the reduction of leukocyte migration to inflammatory sites common in graft rejection.
The adverse effects associated with MM are mainly gastro-intestinal and include nausea, diarrhoea and vomiting (Barron, 1996) thus use in patients with known gastro-intestinal complaints should be carefully considered. As with all immunosuppressants, there may be an increased risk of secondary infection but MM does not appear to be a greater threat in this regard compared to the older more conventional drugs. It is as yet unknown if MM may be teratogenic in humans as it has been in some animal studies thus use in pregnancy is ill advised unless the potential benefit to the mother outweighs the risk to the unborn child (Barron, 1996). It has also been noted that there is an increased risk of the development of lymphoma and other malignancies with MM treatment which is again common with many of the immunosuppressants (Nutley, 1995). This new drug certainly appears to present less side-effects when compared to traditional immunosuppressive agents. The major drawback associated with MM is the high cost: almost five times that of the traditional immunosuppressant azathioprine.
However, considering that one half of kidney transplant patients experience acute episodes of rejection during the first year after transplantation (Nutley, 1995) it would appear that the cost could be well spent in terms of the saving of lives and prevention of suffering. 15 -deoxyspergualin 15 -Deoxyspergualin (DSG) is isolated from bacillus laterosporus and has been successful in the prevention of renal transplant rejection, and may also be beneficial in heart and pancreatic transplantation's (Katzung, 1998). Recent studies have shown DSG to have a unique ability among immunosuppressive drugs to reduce long-term survival and functional tolerance of discordant islet xeno grafts (Thomas et. al. , 1995). The potential of DSG as a treatment for autoimmune diseases is also being investigated (Tepper et. al. , 1995).
Indeed, DSG is proving more effective than tacrolimus (Grebenau, 1999) and less toxic than aziathropine (Thomas, 1995). The mechanisms of action are not entirely understood but appear to result from the suppression of both the humoral and cell-mediated immune responses (Tepper et. al. , 1995). It appears that this new drug needs further rigorous testing but possible future applications particularly in xeno grafts seem to be encouraging.
Sirolimus Sirolimus (rapamycin) is relatively similar to the more traditional immunosuppressants: tacrolimus and cyclosporine. However, it is much more potent and has distinct uses in the management of kidney and heart allograft's (Katzung, 1998). Again, the possibilities of sirolimus as treatment for autoimmune diseases is currently being investigated (Grebenau, 1999) and the drug is currently in phase three trials. The mechanism of action is through cytokine signals which are required for T-cell proliferation (Valentine & Schroeder, 1995), that is, Sirolimus acts as a T-cell inhibitor when used in combination with cyclosporine and steroids (Bertolatus, 2000). Major side effects include increased blood cholesterol and triglyceride levels, leucopenia (decreased white blood cell count) and thrombocytopenia (decreased platelet count) (Kelly, et. al. , 1997).
Thalidomide Thalidomide has a problematic history as it produced severe teratogenic effects when used to alleviate diarrhoea and nausea in pregnant women. However, it has since emerged as an immunosuppressant particularly useful in treatments to prevent lung transplant rejection (Katzung, 1998). Thalidomide may also prove beneficial in the treatment of HIV patients particularly those suffering from chronic weight loss as it increases the immune chemical, tumour necrosis factor-alpha (Kahan, 1999). However, mechanisms of action are not further understood and may involve a change of T-cell response to antigens (Katzung, 1998). Treatment of leukaemia is another area of possible thalidomide use (Grebenau, 1999). Obviously, this drug must not be used in the treatment of pregnant women and may also cause side-effects such as drowsiness and skin rashes (Kahan, 1999).
Antibodies as immunosuppressants Milstein and Kohler increased the pharmacological use of antibodies as immunosuppressants via hybrid oma technology. This concept involves the fusing of antibody-forming and plasmacytoma cells to produce the required antibody for cloning (Katzung, 1998). The implications of such technology are far-reaching as specificity will be greatly increased using these monoclonal antibodies. As yet studies into treatments for multiple sclerosis using this technology have been inconclusive but appear to be fraught with unintended side effects (Patch, 1996).
Anti lymphocyte antibodies have been utilised early after organ transplantation and have had beneficial short term effects but the long term outcomes have been disappointing (Valentine & Schroeder, 1995). IMMUNOMODULATION The immuno modulation branch of pharmacology involves boosting the immune system rather than suppressing it, by using agents to augment the immune response. The potential uses of immuno modulation include the treatment of immunodeficiency disorders, chronic infectious diseases, cancer and AIDS (Katzung 1998). Many cancer patients do not die directly from their cancer but from a secondary infection. It has also been discovered that in the United States of America sixty-five million people suffer from a dysfunctional immune system which can lead to chronic viral infections, AIDS, cancer and autoimmune diseases (Beardsley, 1997) Immmunomodulation & autoimmune disease Traditionally, it has been thought that stimulating the immune system will be harmful for sufferers of autoimmune disorders as it will exacerbate the bodys attack upon sel...
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Research essay sample on Autoimmune Diseases Organ Transplantation
