Caerulomycin A: A Novel Immunosuppressive Agent that Modulates the Activity of Both T Cells and B Cells
Javed N. Agrewala
Institute of Microbial Technology, Chandigarh-160036, India
Abstract:
Immune system of an organism has been developed with surveillance and defense mechanism by recognition and elimination of pathogenic foreign microorganisms such as bacteria and viruses. Therefore, the organism distinguishes own cells or tissues (self-antigens) from foreign microorganism (nonself-antigens), and does not respond to the self-antigens, or respond to them having the failure to mount immune response. Accordingly, the organism has developed an acquired immunity to eliminate nonself-antigens immediately and efficiently. B cells and T cells are important cells of the immune system. Regulation of these cells is a major target for treating and/or preventing a large variety of diseases that require or benefit from an enhanced or reduced immunity, e.g. autoimmune diseases including type I diabetes, multiple sclerosis, asthma, arthritis, myasthenia gravis, lupus erythematosus, psoriasis, colitis, or rejection of transplanted organs, or immuno-deficiency diseases, and cancer. Therefore, there is a strong need for drugs capable of modulating the complex B and T cell responses for the purpose of treating and preventing numerous immunological disorders and diseases. Successful organ transplantation requires effective physiological and pharmacological intervention of the immune system of an organ recipient. One approach to intervention of immune response in an organ transplant recipient, especially a recipient targeted for an allogenic graft, is by the use of immunosuppressive drugs. These drugs are used to prolong survival of transplanted organs in recipients in cases involving, for example, transplants of kidney, liver, heart, lung, bone marrow and pancreas. There are several types of immunosuppressive drugs available for use in reducing organ rejection in transplantation. Such drugs fall within three major classes, namely: antiproliferative agents (azathioprine, cyclophosphamide and methotrexate), anti inflammatory compounds (are prednisone and prednisolone) and inhibitors of lymphocyte activation (FK-506, Cyclosporins). Cyclosporins possess several significant disadvantages. While cyclosporins have provided significant benefits in organ transplantation, cyclosporins are non-specific immunosuppressives. Desirable immune reactions may be reduced against foreign antigens. Tolerated dosages do not provide complete suppression of rejection response. Thus, immunologic reactions to transplanted tissue are not totally impeded, requiring concomitant treatment with prednisone, methylprednisolone, and/or other immunosuppression agents, including monoclonal antibodies such as anti-CD3 or anti-CD5/CD7. Cyclosporins can produce severe side effects in many organ recipients, and show host-variable effects on the liver, kidney, the central nervous system and gastro-intestinal tract. Significant among the adverse side effects are damage to the kidney and liver, hyperplasia of gum tissue, refractory hypertension and increased incidence of infections and malignancy. Thus, the need remains for efficacious and selective immunosuppressive drugs for the treatment of autoimmune diseases and also in organ transplantation, especially for grafts between less-than-perfectly matched donor-recipient pairs. We have identified a novel property of Caerulomycin A as an immunosuppressive agent. Caerulomycin A inhibits the proliferation of activated lymphocytes, especially CD4+ T cells (both Th1 and Th2) and B cells, which are the cornerstone of adaptive immunity. It also suppresses the production of IL-2, IL-12, IL-4 and IFN-g. Further, it delays the onset of rejection of skin allografts in mice. This indicates that Caerulomycin A has implication in transplantation biology and allergic and autoimmune diseases and can be a potent future immunosuppressive drug with substantial clinical applications.
