The Latest Advances In Drug Manipulations Of The I
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 immunomodulators 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 pharmacodynamics involved with each type. The possible clinical uses will be alluded to along with details from recent research.
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).
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 immunopharmacological agents.
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).
The antigen on the surface of the APC triggers TH-cells to produce hormone-like lymphokines (Lessof, 1993). Lymphokines are cytokines, regulators of the immune reactions which are produced by lymphocytes. Examples of these chemicals include interleukins, 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 & Harboe, 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 complement’s ability to attract leukocytes (Lessof, 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 immobilise an antigen therefore preventing attack upon host cells, to block active toxic regions of particular bacteria, and to allow phagocytic attack.
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 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 CD8+) or Helper cells (TH-cells, or CD4+). 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 lymphokines which activate local macrophages (Waller ; Renwick, 1994). Meaning big eaters’ macrophages engulf micro-organisms and secrete lysosomal enzymes, complement components and some lymphokines (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 immunomodulation. 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).
The prototype immunosuppressant, cyclosporine was discovered in the 1970s 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 patient’s 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 immunomodulators 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 mycophenalate mofetil, thalidomide, sirolimus and 15-deoxyspregualin, will be provided and their mechanisms of action, when understood, described.
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 penicillum glaucum (Katzung, 1998), MM, brand name cellcept, has greatly improved the ratio of immunosuppressive activity versus side effects’ (Hoffman & Jones-Reeder, 1998). Administered orally, MM is hydrolysed 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 (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 transplantations (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 xenografts’ (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 xenografts seem to be encouraging.
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 allografts (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 (Valantine & 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, leukopenia (decreased white blood cell count) and thrombocytopeania (decreased platelet count) (Kelly, et. al., 1997).
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 hybridoma’ 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 (Panitch, 1996). Antilymphocyte antibodies have been utilised early after organ transplantation and have had beneficial short term effects but the long term outcomes have been disappointing (Valantine ; Schroeder, 1995).
The immunomodulation branch of pharmacology involves boosting the immune system rather than suppressing it, by using agents to augment the immune response. The potential uses of immunomodulation 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 body’s attack upon self’ cells. However, recent research suggests that autoimmune diseases maybe due to the dysregulation of the immune system, and that poor thymus functioning results in T4Helper cells losing control of humoral immunity so that antibodies lose their specificity and attack host cells (Beardsley, 1997). Thus immunomodulation in this area could be highly effective. It must be stated that this is merely a theory and that extensive testing is still needed in this area before such drugs can be used safely to treat these disorders.
It would appear that immunomodulation is a new and exciting area to be explored with many potential benefits. A selection of these new drugs including levamisole, thymic peptides, roquinimex, and cyclophosphamide will be described in more detail.
Levamisole (eramisole) is an immunomodulating agent administered orally with the effect of increasing the number of T-cells. It has been shown to be effective in the treatment of Hodgkin’s disease, and is approved by the FDA for the treatment of colorectal cancer after surgery. Recently, levamisole has been tested in the treatment of rheumatoid arthritis with some efficacy. The side effects involved include mild nausea, stomach pain, dizziness, headache and fatigue (Katzung, 1998). It would appear that there is insufficient research concerning this drug, thus the likelihood that it will be marketed for clinical use in the near future is markedly reduced.
Thymosin & other thymic peptides
Thymic activity is critical to T cell maturation, only mature cells can effectively combat cancer cells and infectious agents. Thymosin conveys specificity to immature lymphoid stem cells and therefore increases the number of active T-cells (Katzung, 1998). However, it has not been yet approved by the FDA (Beardsley, 1997) despite its successes in trials in treatment of diseases of T-cell deficiency such as DiGeorge’s syndrome (Katzung, 1998). Thymic protein A has proved beneficial in the treatment of hepatitis C, cancer and certain immune disorders via the stimulation of the cell mediated immune system (Beardsley, 1997). Thymopentin and Thymic humoral factor have also been used to treat AIDS as well as cancer and hepatitis. However, other trials suggest that thymosin may stimulate the pituitary-adrenal system, resulting in an increase of serum corticosteroids and the decrease of thymic hormone production. Therefore the impairment of the immune functioning will result from thymic treatments rather than the intended increase of the immune response (Bard et. al., 1990) Such new immunomodulators certainly need extensive research before a more suitable form can be identified.
Cyclophosphamide (cytoxan, neosar) is traditionally an immunosuppressant used to suppress a variety of humoral and cell-mediated immune functions (Dale et. al., 1994). However, new developments have proved the immunomodulating function of the drug. Low doses given prior to immunisation with a tumour vaccine can augment the immune response (Katzung, 1998). As such, cyclophosphamide can be used to treat Hodgkin’s disease, lymphomas, leukemias and other tumours. Rheumatoid arthritis can also be treated by the immunomodulating features of this drug which can be achieved at higher doses than are necessary for immunosuppression (Shorthouse, 1996). Recently, this drug has been used in trials to treat chronic -progressive multiple sclerosis. However, the benefits proved to be inadequate in balance with the side-effects which included hair loss, fever, oral ulcers (Panitch, 1996), nausea, vomiting, thrombocytopenia, leukopenia and anorexia (Shorthouse, 1996). Teratogenic effects make the drug unsuitable for pregnant or breast feeding women and long term toxicities include bladder cancer and acute nonlymphocytic leukemia (Panitsh, 1996). In conclusion it appears cyclophosphamide may have some benefit in short-term immunomodulation, particularly as a cytotoxic agent, but long term, high doses will produce a plethora of side effects.
THC & marijuana
Trials in the United States of America in 1995 have tested the use of marijuana in immunomodulation. THC is the component of interest in marijuana which has been demonstrated to enhance the production and release of pro-inflammatory cytokines from macrophages. The study has also found impairment of immunological functions in persistent marijuana smokers. However, the conclusion is that THC is an excellent tool for studying the mechanisms of immunomodulation, especially altered susceptibility to microbial infection’ (Friedman et. al., 1995) but further intensive study is needed.
Roquinimex (linomide) is not an immunosuppressant, it activates lymphocyte and natural killer cells, therefore acting as an immunomodulator (Panitch, 1996). By stimulating a variety of B and T-cell functions it has been used to treat acute and chronic relapsing multiple sclerosis, with a marked reduction in relapses, disease activity and progression (Katzung, 1998). Although the mechanisms of action themselves are not fully understood it is thought that via activating T-cells these drugs stimulates the production of regulatory cytokines that suppress inflammation and prevent myelin deterioration (Panitch, 1996). Trials in prostate tumour treatment have proved that roquinimex is the most effective drug with a sixty-nine percent inhibition of tumour growth (Joseph ; Isaccs, 1998). Thus roquinimex is emerging as a promising new treatment for cancer and multiple sclerosis.
To conclude, recent literature suggests that research into immunosuppression is more wide spread than in the area of immunomodulation. This newer concept certainly needs further investigation but has many potential benefits especially in the treatment of AIDS. Many other agents such as new vaccines and alternatives to antibiotics are being developed, unfortunately due to certain constraints they are beyond the scope of this review. As understanding of natural immune mechanisms is increased, further manipulation of the immune system will be possible. As the millennium begins it appears that the future of immunopharmacology is promising.
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