Inhibition of apoptosis, activation of NKT cell and upregulation of CD40 and CD40L mediated by M. leprae antigen(s) combined with Murabutide and Trat peptide in leprosy patients.
Protective immunity against intracellular pathogen Mycobacterium leprae is dependent on the activation of T cells. Repeated stimulation of T cells by M. leprae antigens MLCwA (M. leprae total cell wall antigen) and ManLAM (mannose-capped lipoarabinomannan), may lead to apoptosis in leprosy patients. In the present study, inhibition of the Fas-induced apoptosis of peripheral blood mononuclear cells of leprosy patients was investigated using above M. leprae antigen(s), in combination with immunomodulators murabutide (MB) and a Trat peptide in particulate form (liposome). Incubation of the cells with antigen containing the two immunomodulators in particulate form (liposomes) led to decrease in percentage of propidium iodide positive cells and T cells expressing Fas-FasL as well as decreased caspase-8/-3 activities in lepromatous patients, thereby inhibiting apoptosis, while converse was true upon stimulation with soluble antigen. Concurrently, there was an upregulation of antiapoptotic protein Bcl-xL in lepromatous patients, leading to the inhibition of apoptosis. It was also observed that same formulation upregulated the expression of CD40 on B cells and monocytes-macrophages and CD40L on T cells of lepromatous leprosy patients. The same liposomal formulation significantly increased the expression of CD1b and CD1d on monocytes-macrophages as well as percentage of NKT cells secreting IFN-gamma in lepromatous leprosy patients. Thus, the liposomal formulation of antigen with the immunomodulators in vitro promoted the activation of CD40:CD40L pathways and NKT cell function involved in providing cell-mediated immunity to these patients. The same formulation also caused reversal of T cell anergy by inhibiting apoptosis through decreased expression of death receptors (Fas-FasL) and caspase activities (3 and 8) and increased expression of antiapoptotic protein Bcl-xL in these patients.
Chattree
Vineeta
V
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. dnrao311@rediffmail.com
Khanna
Neena
N
Bisht
Vandana
V
Rao
D N
DN
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D019013:CD40 Antigens / Q000235:genetics*; D023201:CD40 Ligand / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D007918:Leprosy / Q000188:drug therapy* / Q000201:enzymology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae / Q000187:drug effects / Q000276:immunology*; D011419:Propidium / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
D000942:Antigens, Bacterial; D015703:Antigens, CD; D019013:CD40 Antigens; D016207:Cytokines; D007155:Immunologic Factors; D051020:bcl-X Protein; D023201:CD40 Ligand; D011419:Propidium; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C033575:murabutide; D053148:Caspase 3; D053181:Caspase 8