Executive Summary : | Cytotoxic T lymphocytes play a pivotal role in keeping infections and malignancies in check. Multiple co-stimulatory and co-inhibitory molecules control the response of T-cells to antigens presented to them.1 CTLA-4 and programmed death-1 (PD-1) are co-inhibitory molecules, often referred to as immune checkpoint inhibitors. Two ligands have the capacity to engage PD-1; PD-1 ligand 1 (PD-L1, CD274) and PD-1 ligand 2 (PD-L2). Membrane bound PD-1 (mPD-1) is expressed on both B and T lymphocytes, being activated simultaneously as these cells receive their stimulatory signals, preventing their overactivation. Production of mPD-L1 is widespread, and is produced by T and B lymphocytes, monocytes, dendritic cells, macrophages. The mPD-L1 expressed by T-regs, tumor cells and macrophages interacts with mPD-1 expressed on cytotoxic T-cells causing tolerance, exhaustion, and apoptosis of cytotoxic T-cells. Chronic infections are those conditions that usually have a course that is uncertain and unlimited in time, and may have periods of remission and acute crises.2 Studies have shown that in chronic infections, immunosenescence plays an important role. Immuno senescence is phenomenon in which there is a progressive remodelling of the immune function, wherein there is a resistance to immune modulation. The possible cause is chronic antigenic stimulation. There is a reduction in the naïve CD8 cells and an increase in CD4 cells.3 This has been seen in HIV and Tuberculosis in which there is upregulation of immunosenescence markers like CD57 and reduced expression of CD127.4 Recent hypothesis is that cytotoxic T cells become anergic, paving the way to chronic long-lasting infections and progressing malignancies. Leprosy is a chronic infection caused by an acid fast organism, Mycobacterium leprae. It can have a spectrum of clinical manifestations depending on the host cell immunity. The Th1 cytokines may lead to a well circumscribed tuberculoid form, whereas a Th2 cytokine predominance shifts the spectrum to a chronic simmering lepromatous form. Mycobacterium leprae increases the expression of regulatory T cells. A prior study has found the increased expression of CTLA-4 on lymphocytes of patients with lepromatous leprosy compared to the tuberculoid pole. Research Questions a) What is the native cutaneous and blood expression of programmed death receptors and its ligands and other markers of immunosenescence in treatment naïve patients having leprosy? b) Does this expression vary across the clinical spectrum of leprosy including the patients presenting with reactions? c) Does this expression determine the treatment response to standard WHO MDT (World Health Organization- Multi Drug Therapy)? d) Does this expression change at the completion of standard WHO MDT? experiments: to study the expression of mPD-1, mPD-L1, and markers of immunosenescence (CD27, CD28, CD57 and Tim-3) in skin and PBMC using ELISA, confocal microscopy, RT-PCR and flow cytometry. |