The treatment of organ rejection with immunosuppressive medication a discussion - Free Essay Example

Since the pioneering experiments of allograft heart transplantation by Christiaan Barnard in 1967, there have been significant advances in the development of human organ transplantation. Indeed, over 35,000 patients in both the US and Europe benefit annually from organ transplantation (Hampton, 2005). Through the transplantation and engraftment of these organs, not only can biological function of organs be restored, but also the quality of life of recipients can be greatly increased. As a result the number of transplantation operations carried out each year has increase exponentially over the past decades. Despite improvements in surgical techniques, the hurdle of immunological rejection by the host of transplanted organs still remains a current obstacle. This represents a challenge both scientifically and clinically and, as a result, is a focus of both the medical and scientific communities. Over the past 60 years, there has been an exponential increase in the development of immunosuppressive drugs in order to treat organ rejection, as well as autoimmune diseases (Gummert et al. 1999). These drugs seek to suppress various components of the immune system in order to prevent rejection in the context of organ transplantation. This essay seeks to examine the broad immunology of transplantation as well as the different classes of immunosuppressive drugs and their associated benefits and side effects. Transplantation is broadly defined as the act of transferring cells, tissues, or organs from one site to another. In the context of organ transplantation, this is generally from one person to another, with transplantation classed as either from a living donor or cadaveric. Although less common, there has been some attempt to transplant organs from other animals, known as xenografts. This was initially attempted given the lack of availability of human donor organs. However, as transplantation occurs between two immunologically distinct persons, a degree of immunological mismatch occurs. Due to this mismatch, the host immune system recognises the donor organ as foreign and, as a result, activates various arms of the immune system. Several types of immune rejection can occur in individuals undergoing organ transplantation. Hyperacute rejection occurs when pre-existing antibodies within the host against donor antigens attack the graft and result in rapid rejection of the graft, typically within a few hours (Murphy et al. 2010). This results in rapid declining function of the graft and is often non-reversible, thereby causing the recipient to lose the graft. In contrast, acute rejection occurs within six months following transplantation and is the result of activated T cells against donor antigens (Murphy et al. 2010). The third type of rejection is known as chronic rejection and, as the name suggests, occurs years after transplantation and is mediated by both antibodies and T cells. In order to encourage graft survival, and prevent the aforementioned from occurring, effective regimes in order to suppress these immune responses have been developed, although as outlined, they often come with significant side effects. Glucocorticoids, such as prednisone, are commonly used in immunosuppressive regimes. These drugs seek to prevent rejection by suppressing various arms of the immune system including T cells, B cells, macrophages, granulocytes and monocytes (Steiner and Awdishu, 2011). These drugs are, therefore considered t o be relatively non-specific and highly potent leading to a range of side effects. Glucocorticoids exert their effects by regulating the activity and expression of various cytokines through inhibition of intracellular signalling pathways such as NF-kB. Through modulation of this complex signalling pathway, the production of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha are greatly reduced (Schacke et al. 2002). Although these drugs feature heavily in clinical practice, they are associated with a significant number of side effects. Prolonged glucocorticoid use can lead to Cushings syndrome: a constellation of symptoms characterised by increased central adiposity, buffalo hump, osteoporosis and a round face (Schacke et al. 2002). These symptoms are due to excess exogenous cortisol within the body and therefore have multiple endocrinological effects on various physiological processes. The concentration of such drugs are therefore closely monitored and patients are encoura ged to monitor for symptoms suggestive of Cushings syndrome. As well as glucocorticoids, drugs known as antimetabolites are frequently used in immunosuppressive regimes. These drugs, such as azathioprine and mercaptopurine, amongst others, were originally developed in the 1950s, but remain used to this day. Azathioprine is commonly used for liver and kidney transplantation (Germani et al. 2009), as well as for the treatment of autoimmune conditions such as rheumatoid arthritis (Whisnant and Pelkey, 1982). Antimetabolites exert their immunosuppressive effects by blocking the synthesis of purine within cells (Murphy et al. 2010). Through the blockage of purine synthesis, DNA replication is unable to take place, thereby preventing expansion of rapidly dividing cells within the immune system. Through the blockade of T and B cell expansion, the level of rejection against organ transplants can be controlled. One considerable side effect associated with the use of azathioprine is the increased risk of skin cancer. A relatively recent review by Ulrich and Stockfleth (2006) has shown that sunlight exposure, pre and post transplantation in patients using azathioprine, correlates with an increased incidence of skin cancer. As exposure to UVA light damages skin cells: these cells are unable to undergo repair following damage, due to inhibition of DNA replication from azathioprine. In the long term, this accumulation of damage results in the increased propensity for patients to develop skin cancer. Current clinical guidelines suggest that clinicians discourage patients in spending prolonged periods of time in the sun following transplantation (Perrett et al. 2008). Along with these classes, of drugs, another category of immunosuppressive medications, known as calcineurin inhibitors, also work efficaciously in organ transplantation. These drugs, which include tacrolimus and cyclosporine, act by inhibiting the protein calcineurin. Calcineurin in activated following the presentation of an antigen by an antigen presenting cell, such as a dendritic cell or macrophage, to a T cell, resulting from an increase in the concentration of intracellular calcium (Reynolds and Al-Daraji, 2002). Following the activation of calcineurin, there is an increase in the production of interleukin 2 (IL-2), which causes the activation of T cells. As a result, this further propagates an immune response. Calcineurin inhibitors are, therefore, useful in dampening an immune response, preventing the activation of T cells against a transplanted organ. Calcineurin inhibitors are popular drugs used in renal transplantation. However, evidence over the past decade has suggested that drugs such as tacrolimus may induce renal failure in some patients (Ponticelli, 2000). Obviously this a key consideration when considering patients who already have poor renal function to being with. As a result, these drugs are often combined with other immunosuppressive agents and tailored to the lowest dosage possible. The understanding into the way in which the immune system functions has been exploited over the past thirty years with the development of monoclonal antibodies. Monoclonal antibodies were first developed in the 1970s through the fusion of rapidly proliferative myeloma cells with B cells to produce hybridomas (Liu, 2014). Antibodies are protein molecules that have a specific antigen-binding region enabling them to have a high degree of specificity. Antibodies have, therefore, been exploited therapeutically in order to target pathogenic molecules within the body. Recently, monoclonal antibodies have been developed to target various components of the immune responses in order to modulate organ rejection seen in patients. In particular, monoclonal antibodies have been developed to target T and B cells. Some examples of these therapeutics are discussed below. Muromonab is a monoclonal antibody, which is specific for cluster of differentiation 3 (CD3), a molecule found primarily on T cells (Murphy et al. 2010). By targeting T cells and preventing their activation against the transplanted organ, there is considerable evidence to show that this can significantly prolong the survival of the organ following transplantation, compared to glucocorticoid steroids (Authors not listed, 1985). However, despite the success of anti-CD3 therapy, there are substantial side effects associated with clinical use. Use of anti-CD3 has been associated with severe fever in patients, as well as the unwanted release of pro-inflammatory cytokines (Norman et al. 2000). As a result the use of anti-CD3 has declined in clinical practice and is reserved for treatment resistant cases of organ rejection. As well as muromonab, another mainstay treatment for organ rejection are antibodies directed against cluster of differentiation number 25 (CD25). Organ rejection is heavily mediated by T cells, in combination with other arms of the immune system (Ingulli, 2010) . When activated, T cells produce large amounts of IL-2, a cytokine that acts in an autocrine fashion to further expand T cells via the IL-2 receptor CD25. Therefore, blockade of CD25 with a monoclonal antibody was hypothesised to offer a novel target in treating immunological rejection by T cells. As a result, daclizumab was developed and was shown by Vincenti et al. in 1998 to be a successful tool in treating renal transplantation compared to using a combination therapy of cyclosporine, azathioprine and corticosteroids. Furthermore, more long term studies have examined the function of renal transplants and concluded that patients on daclizumab showed improved renal function, as established by estimated glomerular filtration rate (GFR) (Ferran et al. 1990). However, like other pharmacological treatments, daclizumab has also been shown to cause a significant number of side effects such as hypertension and insomnia (EPAR for Zenapax). More recently, the scientific community has so ught to develop more refined immunological tools in order to modulate rejection. Through the development of monoclonal antibodies targeting cluster of differentiation 52 (CD52), clinicians are able to target lymphocytes for destruction, sparing the destruction of resident haematopoetic stem cell populations (Flynn and Byrd, 2000). Anti-CD52 drugs were originally developed for multiple sclerosis (Coles et al. 2008) and trials are currently being undertaken to establish their efficacy in organ transplantation. The overarching side effect with immunosuppressive regimes is the relatively blanket level of immunosuppression which they cause. Although immunosuppression is required to maintain organ survival, immunosuppression also results in a reduced ability to fight infections. In particular, pulmonary infections are common in organ transplant patients, with Hoyo et al. (2012) detailing that around 1 in 5 patients in their study developed pulmonary infections. It is clear that clinici ans dealing with organ transplantation patients must remain vigilant for infections. It is similarly clear, therefore, that a fine balance of the level of immunosuppression should be reached: a heavily weighted level will pre-dispose to opportunistic infections, and, conversely, a lightly weighted level will result in organ rejection. With respect to future outlooks in transplantation immunology, the development of pluripotent stem cells has been hypothesised to overcome immunological issues associated with organ transplantation. Through the use of induced pluripotent stem cells (iPS cells) developed by Takahashi et al. (2006) it has been shown that it is possible to differentiate nearly all existing cell types. As these cells are derived from the patient, they are immunologically matched to the individual and, as a result, patients would not require harsh immunosuppressive regimes. Although this technology has not been tested clinically in patients extensively yet, it is hoped t hat within the next twenty years this method will provide an unlimited source of organ replacement for patients. Use of such cells is currently being explored for regeneration of certain organs such as the heart (Masumoto, 2014). Use of these cells will require a significant amount of clinical testing to determine their immunological properties, as well as their propensity to develop into tumours. It is likely, therefore, that the clinical applications of stem cells are still many years away. In conclusion, despite significant improvements in targeted immunosuppressive regimes, significant side effects are associated with current pharmacological treatments. Clearly, as patients treated with these agents are often susceptible to opportunistic infections, their progress must be monitored closely by a clinician who is familiar with such patients, and the complications they can present with. Through our increased understanding of the immune system, alongside new technologies such as stem cell replacement therapy, it is hoped that the immunological issues associated with organ transplantation will in the near future be overcome. Bibliography Authors not listed (1985) A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. Ortho Multicenter Transplant Study Group. N Engl J Med. 313:337à ¢Ã¢â€š ¬Ã¢â‚¬Å"342 Coles, A., Lake, S. and Moran, S. (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. NEJM. 359: 1786-1801. EPAR for Zenapax. European Medicines Agency. 2007. https://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000198/WC500057570.pdf Gummert, J., Ikonen, T. and Morris, R. (1999) Newer immunosuppressive drugs: a review. J Am Soc Nephrol. 10(6):1366-80. Hoyo, I. Sanclemenete, G., Cervera, C. (2012) Opportunistic pulmonary infections in solid organ transplant recipients. Transplant Proc. ;44(9):2673-5 Ferran, C., Dy, M., Merite, S., Sheehan, K., Schreiber, R., Leboulenger, F. (1990) Reduction of morbidity and cytokine release in anti-CD3 MoAb-treated mice by corticosteroids. Transplantation. 50:642à ƒ ¢Ã¢â€š ¬Ã¢â‚¬Å"648. Flynn, J. and Byrd, J. (2000) Campath1H monoclonal antibody therapy. Current. Opinion in Oncology. 12(6) 574-581. Germani, G., Tschochatiz, E., Adreana, L. and Burroughs, A. (2009) Azathioprine in liver transplantation: a reevaluation of its use and a comparison with mycophenolate mofetil. Am J Transplant. 9(8):1725-3 Hampton, T. (2005) Skin cancers ranks rise: immunosuppression to blame. JAMA. 294: 1476-1480. Ingulli, E. (2010) Mechanism of cellular rejection in transplantation. Pediatr Nephrol. 25(1): 61à ¢Ã¢â€š ¬Ã¢â‚¬Å"74. Liu, J. (2014) The history of monoclonal antibody development à ¢Ã¢â€š ¬Ã¢â‚¬Å" Progress, remaining challenges and future innovations. Ann Med Surg (Lond). 3(4): 113à ¢Ã¢â€š ¬Ã¢â‚¬Å"116. Masumoto, H., Ikeda, T., Okano, T., Sakata, R. and Yamashita, J. (2014) Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration. Scientific Reports. 4: 6716/ Murphy KM, P Trave rs, M Walport (Eds.) (2010) Janeways Immunobiology. 8th Edition. New York:Taylor Francis, Inc. Norman, D. J., Vincenti, F., de Mattos, A.M., Barry, J.M., Levitt, D.J., Wedel, N.I. (2000) Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors. Transplantation. 70:1707à ¢Ã¢â€š ¬Ã¢â‚¬Å"1712 Perrett, C., Walker, S., Warwick, J., Harwood, C., Karran, P. and McGregor, J. (2008) Azathioprine treatment photosensitizes human skin to ultraviolet A radiation. BJD. 159(1): 198-204. Ponticelli, C. (2000) Calcineurinà ¢Ã¢â€š ¬?inhibitors in renal transplantation. Too precious to be abandoned. Nephrol. Dial. Transplant. 15 (9): 1307-1309. Reynolds, N. and Al-Daraji, W. (2002) Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. Clin Exp Dermatol. 27(7):555-61. Schacke, H., Docke, W. and Asadullah, K. (2002) Mechanisms involved in the side effects of glucocorticoids. Pharmacology and Therapeutics. 96(1): 22-43. Steiner, R. and Awdishu, L. (2011) Steroids in kidney transplantation. Semin. Immunopathol. 33(2): 157-167. Takahashi, K. and Yamanaka, S. (2006) Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 126(4): 663-676. Ulrich, C. and Stockfleth, E. (2007) Azathioprine, UV light, and skin cancer in organ transplant patientsà ¢Ã¢â€š ¬Ã¢â‚¬ do we have an answer? Nephrol. Dial. Transplant. 22 (4): 1027-1029 Vincenti F, Kirkman R, Light S, Bumgardner G, Pescovitz M, Halloran P. (1998) Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med. 338:161à ¢Ã¢â€š ¬Ã¢â‚¬Å"165 Whisnant, J. and Pelkey, J. (1982) Rheumatoid arthritis: treatment with azathioprine (IMURAN (R)). Clinical side-effects and laboratory abnormalities. Ann Rheum Dis. 41(Suppl 1): 44à ¢Ã¢â€š ¬Ã¢â‚¬Å"47.

Designing A New Automated Customer Service System

In the modern business scape, the reality for many companies is to design practices in accordance with customer expectations, specifically with regards to the ever-increasing need for digital options. This is the case for many industries, with many pondering on how to go about addressing the issue. Bogers Media is one such company to have taken the liberty of not only addressing but also designing, with the intent to implement, a new automated customer service system based on machine learning. Of course, this is not the first of its kind but, if used correctly, it may be among the first in Bogers’ particular industry. Automated customer service systems have been integrated into various companies’ strategies yielding optimal results. Starbucks saw a measurable profit increase after implementing their Mobile Order and Pay program. 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Analysis Of A Doll s House - 1005 Words

A Doll’s House is an iconic play focusing on the themes of respect and reputation, lies and deceit, men and masculinity, and women and femininity. It emphasizes physical aspects of women, while excluding influence on the men s appearance, giving insight into the time period. It shows how society judged others while presenting information about how reputation influenced relationships and marriage, leaving the audience pondering what would have happened to the Helmer family if Nora had been unattractive. Both men and women were harshly judged, in different ways, and this judgment impacted relationships and how they functioned. From analysis of the play, the audience can gather that the people of the time period were very materialistic. The female roles in the play are objectified, and treated like play things. The husband of the protagonist, Torvald, tells Nora â€Å"Why shouldn t I look at my dearest treasure? ­Ã‚ ­at all the beauty that is mine, all my very own?† (Ibsen, 62). 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Elasticity Economics Theory and Applications

Question: Discuss about the Elasticity Economics for Theory and Applications. Answer: Introduction: The place where transaction of goods, commodities and services takes place has been termed as market in economics. In other words, it is the place where interaction and trade between the two major groups namely the buyer and seller takes place. Market is the basic and very important concept in economics. It is the place where equilibrium is restored between the demand and the supply of goods and commodities. According to Pigou (2013) if the market is allowed to operate under free hand, any economy is able to reach its equilibrium stage and retain the position. Price of any commodity is decided here with the help of price mechanism (Mankiw 2014). Assuming that the market is operating under free hand and laissez faire the way in which equilibrium is maintained through price mechanism has been shown in the diagram below: In the given figure, DD and SS are the demand and supply curves respectively intersecting at point E and giving the economy the equilibrium output Qo and price Po. Let it be assumed that due to some reason the price has escalated to P1. When the economy is allowed to work under free hand, the quantity demanded is going to be Q1 whereas the quantity supplied Q2. In other words there is going to be an excess supply of (Q2-Q1) within the economy and hence the sellers will be forced to reduce the price to get their products sold. Similar incidence happens if price is below Po where due to excess demand the sellers get the power to increase the price. In any of this scenario the price mechanism works and equilibrium is restored at price Po. The given two cases talks about the ways in which peoples choices are determined while they decide to purchase and goods. People always have non-satiated wants but are restricted by the availability of resources and hence needs to make choices guided by certain criterion (Bernanke, Antonovics and Frank 2015). Those assumptions are: Consumers are rationale Consumer are non-satiated There is availability of other goods either substitute or compliment People have perfect information Existence of laissez faire and ceteris paribus Assuming the existence of these basic assumptions, the two cases has been discussed below. Beef and Lamb are two kinds of meat serving the same purpose and can be considered as substitute commodity. Hence, when price of beef rises from Po to P1, the quantity of beef demanded falls and the quantity of lamb demanded increases from Qo to Q1. That is the demand curve of the substitute good lamb is going to be upward sloping when constructed against the price of beef. A meal at a restaurant is not a necessity good but it does falls under normal goods. Hence, with the fall in price of food item there is going to be a increase in demand for restaurant meal as shown in the above figure. On other hand with the increase in income of people (from Yo to Y1), there is an increase in the number of visit in restaurant (from Qo to Q1). In other words, there is a positive relation between the income earned and demand for restaurant meals. The table below has been constructed to show the total revenue generated at each step and the change in the elasticity for demand in the economy for that particular good. The total revenue has been calculated as the product of the total quantity sold and the price charged per unit of the good at that stage (Saada 2013). On other hand, the elasticity of demand which highlights the responsiveness of the goods with respect to the variation in the price has been calculated by the following formula (Sowell 2014): Price Quantity demanded Elasticity Total revenue $10 10,000 -3 100,000 $9 13,000 -2.76 117,000 $8 17,000 -2.35 136,000 $7 22,000 -0.95 154,000 $6 25,000 150,000 Table 1: Relation between TR Elasticity Source: Created by the Author The elasticity is interpreted by taking the absolute value of that column. Hence, at price $10 the good is highly elastic in nature and as the price declined the elasticity of the goods declined too. Another thing that can be observed is that with the decrease in price of the good the revenue generated increased. Hence it can be stated from the table that theres an inverse relation between the TR and the elasticity of the good. As TR increases with decrease in the price of goods, the elasticity of the good gets reduced. Martha, an experienced pastry Chef went for one year leave and had to forgo $60,000 salary. She earned net revenue of $ 80,000 from publication of books and magazines. The profit she earned has been analyzed from two different views as follows: Rent $6000 Cost of computer $4000 Forgone Interest $400 Stationary $2000 Total $124,00 Table 2: Direct Cost incurred by Martha Source: Created by the Author Accountants View Economists View Revenue $80,000 Revenue $80,000 Direct Cost $12,400 Costs (Opportunity + Direct) $ 72400 Profit $ 676,00 Profit $ 7,600 Table 3: Profit of Martha Source: Created by the Author References: Bernanke, B., Antonovics, K. and Frank, R., 2015.Principles of macroeconomics. McGraw-Hill Higher Education. Mankiw, N.G., 2014.Principles of macroeconomics. Cengage Learning. Pigou, A.C., 2013.The economics of welfare. Palgrave Macmillan. Saada, A.S., 2013.Elasticity: theory and applications(Vol. 16). Elsevier. Sowell, T., 2014.Basic economics. Basic Books.