The Immune System Essay, Research Paper
INTRODUCTIONIn order to supply a elaborate analysis of recent pharmacological developments affecting the human immune system, it is foremost necessary to present the innate and adaptative immune responses. Immunosuppressants and immunomodulators will be differentiated between and a choice of new and frequently experimental drugs belonging to each class will be provided. Specific drugs will be described including the pharmacokinetics and pharmacodynamics involved with each type. The possible clinical utilizations will be alluded to along with inside informations from recent research.
INNATE IMMUNITYInnate unsusceptibility is the first line of defense mechanism and comprises physical ( tegument ) , biochemical ( complement, muramidase ) and cellular ( macrophages, neutrophils ) mechanisms ( Katzung, 1998 ) . All these mechanisms are non-specific, anti-microbial agents which work in concurrence with adaptative immune responses to supply a more effectual system ( Downie et. al. , 1995 ) .
ADAPTIVE IMMUNITYThe adaptative immune system is split into two mechanisms: humoral unsusceptibility and cell-mediated unsusceptibility. A basic apprehension of these constructs is necessary for the intent of understanding the specific effects of different immunopharmacological agents.
HUMORAL IMMUNITYHumoral or antibody-mediated unsusceptibility is associated with B-lymphocyte cells. Antigens are foreign molecules that initiate an immune response, they have built-in immunogenicity ( Tortora & A ; Grabowski, 1996 ) . Upon contact with an antigen, B-cells divide to bring forth a ringer of plasma cells capable of the production of antibodies. Antibodies are Igs, modified blood proteins with a specific action against antigens. Five chief sub-types of Igs have been identified of which IgG is the most abundant in bodily fluids ( Hopkins, 1995 ) . Several cells are known to originate the procedure of plasma cell distinction and are known jointly as antigen showing cells ( APCs ) ( Waller & A ; Renwick, 1994 ) .
LymphokinesThe antigen on the surface of the APC triggers TH-cells to bring forth hormone-like lymphokines ( Lessof, 1993 ) . Lymphokines are cytokines, regulators of the immune reactions which are produced by lymph cells. Examples of these chemicals include interleukins, interferon and tumour mortification factors. Their action involves the ordinance of the proliferation, distinction and activity of leucocytes ( Dale et. al. , 1994 ) . The nature of lymphocyte stimulation will find which category of Ig will be produced ( Waller & A ; Renwick, 1994 ) .
The function of complement & A ; antibody-antigen complexesAntibodies have two distinguishable maps: to recognize and unite with an antigen, and to trip a defense mechanism mechanism for illustration by triping the complement sequence ( Dale et. al. , 1994 ) . This sequence involves more than 30 proteins ( Mollnes & A ; Harboe, 1996 ) and has the map of the devastation and remotion of occupying micro-organisms and subcellular dust and to advance clearance of antigen-antibody composites ( Dale et. al. , 1994 ) . These maps are achieved chiefly via complement? s ability to pull leucocytes ( Lessof, 1993 ) . The interaction of antibody with specific antigen consequences in the formation of the antibody-antigen composite. This composite has several maps: for case, to immobilize an antigen hence forestalling attack upon host cells, to barricade active toxic parts of peculiar bacteriums, and to let phagocytic onslaught.
Memory cellsOnce the antigens have been destroyed the plasma cells disappear go forthing a few as memory cells which enable a fleet response upon 2nd exposure to the antigen ( Trounce, 1997 ) . Memory cells are the footing of active immunization against bacteriums ( Downie et. al. , 1994 ) . Humoral unsusceptibility is most efficient against antigens dissolved in organic structure fluids, that is extracellular pathogens, chiefly bacteriums whereas cell-mediated unsusceptibility is most effectual against intracellular pathogens such as viruses ( Tortora & A ; Grabowski, 1996 ) .
CELL-MEDIATED IMMUNITYCell-mediated unsusceptibility is chiefly concerned with T-lymphocytes. It is this signifier of unsusceptibility that is thought to be responsible for tissue organ transplant rejection ( Tortora & A ; 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 effecter cells as do the B-cells. However, T-cells produce a assortment of effecter cells ( Downie et. Al. , 1995 ) .
TC-cells & A ; TH-cells The cells produced are chiefly Cytotoxic cells ( TC-Cells or CD8+ ) or Helper cells ( TH-cells, or CD4+ ) . TC-cells recognise and destruct virally infected host cells, hence they are besides known as killer-cells ( Trounce, 1997 ) . It is besides thought that cancerous cells can be destroyed by the same mechanism ( Dale et. Al. ,1994 ) . TH-cells release lymphokines which activate local macrophages ( Waller & A ; Renwick, 1994 ) . Meaning? large feeders? macrophages engulf microorganisms and secrete lysosomal enzymes, complement constituents and some lymphokines ( Dale et, al. , 1994 ) .
IMMUNOSUPPRESSION & A ; IMMUNOMODULATIONBy supplying an overview of the adaptative immune responses it becomes evident that two countries of pharmacological question are of involvement: immunosuppression and immunomodulation. The former construct involves developing agents that suppress the immune responses. This country is of import in the intervention of organ and tissue graft rejection and besides the intervention for certain diseases ensuing from immune system abnormalities. The latter country involves agents that augment or alter certain constituents of the immune system and are hence of import in malignant neoplastic disease and AIDS direction ( Katzung, 1998 ) .
NEW IMMUNOSUPPRESSANTSThe paradigm immunosuppressor, cyclosporine was discovered in the 1970s Almost three decennaries subsequently there is much probe into the development of novel more effectual immunosuppressive drugs ( Dale et. al. , 1994 ) . Traditionally immunosuppressors have been shown to be of import in protracting the life of transplanted variety meats. However, strictly by their nature they greatly weaken the patient? s defense mechanism mechanism and hence increase the hazard of infection by timeserving pathogens ( Downie et. al. , 1995 ) . Traditional thought advocates these drugs in the intervention of autoimmune diseases where the immune system produces antibodies against assorted? ego? tissues ( Trounce, 1997 ) . However, new attacks ( to be discussed subsequently ) prefer the usage of immunomodulators to handle these upsets. Unfortunately many immunosuppressors are non-specific and lead to curative incompatibilities that produce a broad scope of pharmacokinetic and pharmacodynamic fluctuations between different persons ( Kahan, 1999 ) . Thus the latest drugs are being developed with more specificity in head. A choice of these new drugs including mycophenalate mofetil, thalidomide, sirolimus and 15-deoxyspregualin, will be provided and their mechanisms of action, when understood, described.
Mycophenolate mofetilMycophenolate Mofetil ( MM ) is a freshly developed immunosuppressor which has been proven to be assuring in the direction of organ organ transplant. Introduced in 1997, MM has been chiefly utilized in kidney organ transplant interventions in concurrence with cyclosporine and corticoids ( Hoffman & A ; Jones-Reeder, 1998 ) . When used in the combination described, MM has? well reduced the incidence of kidney rejection within the first six months following organ transplant? ( Nutley, 1995 ) . This new drug has besides been the topic of surveies affecting liver organ transplant where it proved to cut down the incidence of rejection when combined with tacrolimus and steroids without increasing the hazard of secondary infections ( Jain et. al. , 1997 ) . In comparative tests with Imuran, MM has proved to be more selective and efficaciously decreases episodes of rejection in nephritic graft patients ( Barron, 1996 ) . In carnal surveies MM has been used successfully for bosom and pancreatic cell organ transplant but farther tests are needed to turn out efficaciousness before usage on human patients. ( Saltiel, 1994 ) . Other recent surveies involve the usage of MM to handle autoimmune diseases such as arthritic arthritis ( Dureza et. al. , 1999 ) .
Isolated from the mold penicillum glaucum ( Katzung, 1998 ) , MM, trade name name cellcept, has? greatly improved the ratio of immunosuppressive activity versus side effects? ( Hoffman & A ; Jones-Reeder, 1998 ) . Administered orally, MM is hydrolysed to the active metabolite mycophenolic acid in the liver and gastro-intestinal piece of land and excreted by the kidney in piss. ( Barron, 1996 ) . By suppressing nucleic acerb synthesis via merely the de nova pathway, MM can selectively suppress T and B-cell activity ( Saltiel, 1994 ) . The consequence of this action leads to the bar of T and B-cell proliferation, the suppression of antibody formation, and the decrease of leukocyte migration to inflammatory sites common in graft rejection.
The inauspicious effects associated with MM are chiefly gastro-intestinal and include sickness, diarrhea and emesis ( Barron, 1996 ) therefore usage in patients with known gastro-intestinal ailments should be carefully considered. As with all immunosuppressors, there may be an increased hazard of secondary infection but MM does non look to be a greater menace in this respect compared to the older more conventional drugs. It is as yet unknown if MM may be teratogenic in worlds as it has been in some carnal surveies therefore use in gestation is sick advised unless the possible benefit to the female parent outweighs the hazard to the unborn kid ( Barron, 1996 ) . It has besides been noted that there is an increased hazard of the development of lymphoma and other malignances with MM intervention which is once more common with many of the immunosuppressors ( Nutley, 1995 ) . This new drug surely appears to show less side-effects when compared to traditional immunosuppressive agents.
The major drawback associated with MM is the high cost: about five times that of the traditional immunosuppressant Imuran. However, sing that? one half of kidney graft patients see acute episodes of rejection during the first twelvemonth after organ transplant? ( Nutley, 1995 ) it would look that the cost could be good spent in footings of the economy of lives and bar of agony.
15-deoxyspergualin15-Deoxyspergualin ( DSG ) is isolated from B laterosporus and has been successful in the bar of nephritic graft rejection, and may besides be good in bosom and pancreatic organ transplants ( Katzung, 1998 ) . Recent surveies have shown DSG to hold? a alone ability among immunosuppressive drugs to cut down long-run endurance and functional tolerance of discordant islet heterografts? ( Thomas et. al. , 1995 ) . The potency of DSG as a intervention for autoimmune diseases is besides being investigated ( Tepper et. al. , 1995 ) . Indeed, DSG is turn outing more effectual than tacrolimus ( Grebenau, 1999 ) and less toxic than aziathropine ( Thomas, 1995 ) . The mechanisms of action are non wholly understood but appear to ensue from the suppression of both the humoral and cell-mediated immune responses ( Tepper et. al. , 1995 ) . It appears that this new drug needs further strict proving but possible future applications peculiarly in heterografts seem to be encouraging.
SirolimusSirolimus ( rapamycin ) is comparatively similar to the more traditional immunosuppressors: tacrolimus and cyclosporine. However, it is much more powerful and has distinguishable utilizations in the direction of kidney and bosom homografts ( Katzung, 1998 ) . Again, the possibilities of sirolimus as intervention for autoimmune diseases is presently being investigated ( Grebenau, 1999 ) and the drug is presently in stage three tests. The mechanism of action is through cytokine signals which are required for T-cell proliferation ( Valantine & A ; 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 cholesterin and triglyceride degrees, leucopenia ( reduced white blood cell count ) and thrombocytopeania ( reduced thrombocyte count ) ( Kelly, et. al. , 1997 ) .
ThalidomideThalidomide has a debatable history as it produced terrible teratogenic effects when used to relieve diarrhea and sickness in pregnant adult females. However, it has since emerged as an immunosuppressant peculiarly utile in interventions to forestall lung transplant rejection ( Katzung, 1998 ) . Thalidomide may besides turn out beneficial in the intervention of HIV patients peculiarly those enduring from chronic weight loss as it increases the immune chemical, tumour mortification factor-alpha ( Kahan, 1999 ) .However, mechanisms of action are non farther understood and may affect a alteration of T-cell response to antigens ( Katzung, 1998 ) . Treatment of leukemia is another country of possible thalidomide usage ( Grebenau, 1999 ) . Obviously, this drug must non be used in the intervention of pregnant adult females and may besides do side-effects such as sleepiness and tegument roseolas ( Kahan, 1999 ) .
Antibodies as immunosuppressantsMilstein and Kohler increased the pharmacological usage of antibodies as immunosuppressors via? hybridoma? engineering. This construct involves the fusing of antibody-forming and plasmacytoma cells to bring forth the needed antibody for cloning ( Katzung, 1998 ) . The deductions of such engineering are far-reaching as specificity will be greatly increased utilizing these monoclonal antibodies. As yet surveies into interventions for multiple induration utilizing this engineering have been inconclusive but appear to be fraught with unintended side effects ( Panitch, 1996 ) . Antilymphocyte antibodies have been utilised early after organ organ transplant and hold had good short term effects but the long term results have been dissatisfactory ( Valantine & A ; Schroeder, 1995 ) .
IMMUNOMODULATIONThe immunomodulation subdivision of pharm
acology involves hiking the immune system instead than stamp downing it, by utilizing agents to augment the immune response. The possible utilizations of immunomodulation include the intervention of immunodeficiency upsets, chronic infective diseases, malignant neoplastic disease and AIDS ( Katzung 1998 ) . Many malignant neoplastic disease patients do non decease straight from their malignant neoplastic disease but from a secondary infection. It has besides been discovered that in the United States of America 65 million people suffer from a dysfunctional immune system which can take to chronic viral infections, AIDS, malignant neoplastic disease and autoimmune diseases ( Beardsley, 1997 )
Immmunomodulation & A ; autoimmune diseaseTraditionally, it has been thought that exciting the immune system will be harmful for sick persons of autoimmune upsets as it will worsen the organic structure? s onslaught upon? ego? cells. However, recent research suggests that autoimmune diseases possibly due to the dysregulation of the immune system, and that hapless Thymuss working consequences in T4Helper cells losing control of humoral unsusceptibility so that antibodies lose their specificity and onslaught host cells ( Beardsley, 1997 ) . Thus immunomodulation in this country could be extremely effectual. It must be stated that this is simply a theory and that extended testing is still needed in this country before such drugs can be used safely to handle these upsets.
It would look that immunomodulation is a new and exciting country to be explored with many possible benefits. A choice of these new drugs including levamisole, thymic peptides, roquinimex, and cyclophosphamide will be described in more item.
LevamisoleLevamisole ( eramisole ) is an immunomodulating agent administered orally with the consequence of increasing the figure of T-cells. It has been shown to be effectual in the intervention of Hodgkin? s disease, and is approved by the FDA for the intervention of colorectal malignant neoplastic disease after surgery. Recently, levamisole has been tested in the intervention of arthritic arthritis with some efficaciousness. The side effects involved include mild sickness, tummy hurting, giddiness, concern and weariness ( Katzung, 1998 ) . It would look that there is deficient research refering this drug, therefore the likeliness that it will be marketed for clinical usage in the close hereafter is markedly reduced.
Thymosin & A ; other thymic peptidesThymic activity is critical to T cell ripening, merely mature cells can efficaciously battle malignant neoplastic disease cells and infective agents. Thymosin conveys specificity to immature lymphoid root cells and therefore increases the figure of active T-cells ( Katzung, 1998 ) . However, it has non been yet approved by the FDA ( Beardsley, 1997 ) despite its successes in tests in intervention of diseases of T-cell lack such as DiGeorge? s syndrome ( Katzung, 1998 ) . Thymic protein A has proved good in the intervention of hepatitis C, malignant neoplastic disease and certain immune upsets via the stimulation of the cell mediated immune system ( Beardsley, 1997 ) . Thymopentin and Thymic humoral factor have besides been used to handle AIDS every bit good as malignant neoplastic disease and hepatitis. However, other tests suggest that thymosin may excite the pituitary-adrenal system, ensuing in an addition of serum corticoids and the lessening of thymic endocrine production. Therefore the damage of the immune operation will ensue from thymic interventions instead than the intended addition of the immune response ( Bard et. al. , 1990 ) Such new immunomodulators surely need extended research before a more suited signifier can be identified.
CyclophosphamideCyclophosphamide ( cytoxan, neosar ) is traditionally an immunosuppressor used to stamp down a assortment of humoral and cell-mediated immune maps ( Dale et. al. , 1994 ) . However, new developments have proved the immunomodulating map of the drug. Low doses given prior to immunization with a tumour vaccinum can augment the immune response ( Katzung, 1998 ) . As such, cyclophosphamide can be used to handle Hodgkin? s disease, lymphomas, leukaemia and other tumors. Rheumatoid arthritis can besides be treated by the immunomodulating characteristics of this drug which can be achieved at higher doses than are necessary for immunosuppression ( Shorthouse, 1996 ) . Recently, this drug has been used in tests to handle chronic -progressive multiple induration. However, the benefits proved to be unequal in balance with the side-effects which included hair loss, febrility, unwritten ulcers ( Panitch, 1996 ) , sickness, purging, thrombopenia, leucopenia and anorexia ( Shorthouse, 1996 ) . Teratogenic effects make the drug unsuitable for pregnant or chest feeding adult females and long term toxicities include vesica malignant neoplastic disease and acute nonlymphocytic leukaemia ( Panitsh, 1996 ) . In decision it appears cyclophosphamide may hold some benefit in short-run immunomodulation, peculiarly as a cytotoxic agent, but long term, high doses will bring forth a overplus of side effects.
THC & A ; marijuanaTrials in the United States of America in 1995 have tested the usage of marihuana in immunomodulation. THC is the constituent of involvement in marihuana which has been demonstrated to heighten the production and release of proinflammatory cytokines from macrophages. The survey has besides found damage of immunological maps in relentless marihuana tobacco users. However, the decision is that THC is an? first-class tool for analyzing the mechanisms of immunomodulation, particularly altered susceptibleness to microbic infection? ( Friedman et. al. , 1995 ) but further intensive survey is needed.
RoquinimexRoquinimex ( linomide ) is non an immunosuppressor, it activates lymphocyte and natural slayer cells, hence moving as an immunomodulator ( Panitch, 1996 ) . By exciting a assortment of B and T-cell maps it has been used to handle acute and chronic get worsing multiple induration, with a pronounced decrease in backslidings, disease activity and patterned advance ( Katzung, 1998 ) . Although the mechanisms of action themselves are non to the full understood it is thought that via triping T-cells these drugs stimulates the production of regulative cytokines that suppress redness and prevent medulla impairment ( Panitch, 1996 ) . Tests in prostatic tumor intervention have proved that roquinimex is the most effectual drug with a 69 per centum suppression of tumour growing ( Joseph & A ; Isaccs, 1998 ) . Thus roquinimex is emerging as a promising new intervention for malignant neoplastic disease and multiple induration.
CONCLUSIONTo conclude, recent literature suggests that research into immunosuppression is more broad spread than in the country of immunomodulation. This newer construct surely needs farther probe but has many possible benefits particularly in the intervention of AIDS. Many other agents such as new vaccinums and options to antibiotics are being developed, unluckily due to certain restraints they are beyond the range of this reappraisal. As apprehension of natural immune mechanisms is increased, farther use of the immune system will be possible. As the millenary begins it appears that the hereafter of immunopharmacology is assuring.
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