Manzoor Ahmad Mir, PhD
College of Applied Medical Sciences, Majmaah University, KSA, Department of Bioresources University of Kashmir, Srinagar India
Raid S. Al Baradie, PhD
College of Applied Medical Sciences, Majamaah University, Almajmaah, Kingdom of Saudi Arabia
Abdul Rahman O. Alharbi, MD
Department of Medicine, Majamaah University, Kingdom of Saudi Arabia
Series: Allergies and Infectious Diseases
Causing about 9 million deaths annually, Cancer is a major health problem worldwide and one of the most prominent causes of mortality in children and adults. The transformation of normal cells to cancer cells may arise due to dysregulation of oncogenes, tumor suppressors and/or stability genes. These transformed cells are sensed by the cells of the immune system, especially T cells, through specific receptors for an effective immune response. Unfortunately, even after the interaction with T cells, an effective immune response is not generated. Signaling through CD80 in B cell lymphomas can retard their proliferation by upregulating expression of pro-apoptotic molecules and downregulating antiapoptotic molecules, therefore inducing apoptosis. Considering the importance of costimulation in the regulation of immune responses against relapsed cancer, the manipulation of this pathway to increase immunity, regress the growth, augment the expression of pro-apoptotic molecules and induce the apoptosis of lymphomas represents a potential therapeutic approach.
Therapeutic modalities targeting the B7 and CD28 costimulatory families of ligands and receptors are showing promise in the clinic. The encouraging results in targeting the B7/CD28/CTLA-4 pathway in autoimmune diseases like Psoriasis, Multiple Sclerosis and Rheumatoid Arthritis underscore the importance of this costimulatory pathway, and validate the pathogenic contributions of T cells in the etiology of these diseases. This novel strategy of costimuilation activation/inhibition can be effectively exploited to develop immunotherapy either using humanized antibodies against CD80, CD86 and CD40 or CD28 fusogenic proteins for the treatment of intracellular pathogens like M. tuberculosis, HIV, L. donovani, T. cruzi, etc.
This strategy can also be used as an alternative strategy or in combination with the drugs. Since this approach is based on modulating the immune system of the hosts rather than targeting the pathogen, it significantly diminishes the chance emergence of drug resistant strains of pathogens. If applied properly, this approach may overcome the rising menace of infectious diseases. To develop alternative or adjunct (with drugs) therapies using costimulatory molecules, an intensive effort has been undertaken in last decade to understand how intracellular pathogens exploit costimulatory molecules which are the tour de force of the immune system. The potent role of costimulatory molecules is aptly established in the optimum activation of T cells and APCs; the cells that play a cardinal role in curbing the infections. Hence, immunotherapy involving costimulatory molecules can be a breakthrough strategy to treat various diseases, minimizing side effects inflicted by drug therapies and restricting the emergence of drug resistance.
To translate this field into the clinic, it is urgent to develop novel methods to target the currently-appreciated costimulatory pathway and deeply understand the pathophysiology of these diseases involving costimulatory molecules. Despite the complex roles and interactions within the CD28 and B7 costimulatory families, we predict that novel approaches targeting these families will yield new therapies for the treatment of inflammation, autoimmunity, transplantation, cancer and other infectious diseases. (Imprint: Nova Biomedical )