Rejection response, antibody

What is the mechanism by which inert or relatively inert foreign bodies exert their antifertility function One possible explanation is the induction of a mild antibody-rejection response to the presence of an indwelling, reasonably large surface-area, foreign protein—the configurationally distorted glycoproteinaceous layer that is spontaneously acquired by the lUD immediately after insertion from uterine secretions. 

Corticosteroids also exert inhibitory effects on the overall immune process. These drugs impair the function of the leukocytes responsible for antibody production and destruction of foreign cells. As a result, corticosteroids are also used therapeutically in the prevention of organ transplant rejection. 

Antibodies have and likely will find additional use in transplantation-related medicine. In general, cell-mediated immunological mechanisms are responsible for mediating rejection of transplanted organs. In many instances, transplant patients must be maintained on immunosuppressive drugs (e.g. some steroids and, often, the fungal metabolite cyclosporine). However, complications may arise if a rejection episode is encountered that proves unresponsive to standard immunosuppressive therapy. Orthoclone OKT-3 was the first monoclonal antibody-based product to find application in this regard. 

Muromonab (Orthoclone OKT3 ) is a mouse monoclonal antibody that kills T lymphocytes, cells that are a part of the immune response. Muromonab, the first monoclonal antibody approved for use as a drug, is used to treat rejection of a donated kidney, liver, or... 

OKT-3 was first approved for general medical use in the USA in 1986. Its indication was the treatment of acute kidney transplant rejection (Table 10.4). OKT-3 is produced via ascites grown in mice. The intact antibody is subsequently purified by a combination of ammonium sulphate fractionation and anion exchange chromatography. Despite its therapeutic effectiveness, the product does display some limitations. Its antigenicity in humans (the HAMA response) is one obvious factor which limits its prolonged use. 

Cyclosporine (Sandimmune) is a potent inhibitor of antibody- and cell-mediated immune responses and is the immunosuppressant of choice for the prevention of transplant rejection. It also has application in the treatment of autoimmune diseases. 

Clinical pharmacology Basiliximab is a chimeric (mouse/human) interleukin-2 receptor antagonist. It is directed against the interleukin-2 receptor-alpha chain (CD25) on activated T-lymphocytes, and is a potent inhibitor of interleukin-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection. Another anti-CD25 monoclonal antibody, dacUzumab (Zenapax), has the same indication as basiliximab. 

As is implied by its name, the first TNF-a-dependent mechanism described was the induction of tumor necrosis in vivo through its role in tumor vasculature. However the mechanisms of the in vitro toxicity of TNF-a to tumor cells imply apoptosis rather than necrosis [97], Tumor necrosis in SCID (severe combined immuno-deficiency) mice treated with LPS does not lead to the rejection of tumors [98], Furthermore, necrosis and tumor regression must be dissociated since anti-IFN-y antibodies inhibit LPS-induced regression of Meth A sarcoma in mice, but not the necrotic hemorrhage attributed to TNF-a. It is now accepted that the antitumoral effect of TNF-a is indirect and dependent on acquired immune response. Matsumoto et al. [99] reported that, while TNF-a itself has no effect on hepatoma KDH-8 tumor cells in vitro, the antitumoral effect of the lipid A ONO-4007 against KDH-8 tumors in vivo is inhibited by anti-TNF-a antibodies in WKAH rat, showing an indirect effect of TNF-a. 

Type IV Reactions Also termed delay-type hypersensitivity reaction, these take 48-72 h to develop and are not antibody-mediated. Antigens are recognized by CD4+ and/or CD8+ cells in the context of MHC class restrictions on APCs. These reactions are T-cell-mediated where activated T cells release cytokines, resulting in the development of granulomas from macrophages. These mechanisms are responsible for symptoms that may include transplant rejection, contact dermatitis, leprosy, tuberculosis and sarcoidosis. 

The above-mentioned observations were also described in humans by P.B. Medawar in the 1940s. Based on his observations in humans, and later in animal experiments, he concluded that the graft rejection was a result of immune response, which eventually led to the discovery of MHC. The development of acquired immune response to transplanted tissue results in the rejection of the tissue where cytotoxic T cells, inflammatory T cells and antibodies play a major role in the rejection process. 

After tissue transplantation, the severity and the period of rejection depend on the tissue type, and this process involves the specificity and memory components of the immune response. Avrion Mitchison in the 1950s observed that allograft immunity could be transferred by the components of the cellular immune response, and antibodies present in the serum that were part of the humoral response were not associated with this process. Future studies delineated the role of T lymphocytes in the allograft rejection process, and the role of both CD4+ and CD8+ cells was established. 

In some cases, a slow rejection phase begins many months or even years after transplantation when acute rejection has subsided. The chronic rejection appears to be due to the slow buildup of antibodies against the graft antigens and/or due to cell-mediated immune responses by the recipient. It does not respond well to the immunosuppressive drugs, and a new transplant is needed following chronic rejection reaction. 

Antibody responses in the H. diminuta mouse system have been reported from a number of workers and isotypes of IgA, IgG and IgM have been found on this cestode. Moreover, their titres increased coincidently with worm rejection and darkened areas suggested that these surface binding antibodies have a functional role in inducing morphological alterations. It is not known, however, whether the presence of these antibodies on the surface is due to specific or non-specific absorption (555). In this system, passive protection of mice by transfer of immune sera has not been demonstrated. 

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