title: Reversal of T cell anergy in leprosy patients: in vitro presentation with Mycobacterium leprae antigens using murabutide and Trat peptide in liposomal delivery.
abstract: Mycobacterium leprae, the causative agent of leprosy resides and multiplies within the host monocytes and macrophages, thereby evading host immune system. Cell-mediated immune response (CMI) plays a vital role as evidenced from the high CMI in BT/TT (borderline and tuberculoid) patients and conversely low in BL/LL (borderline and lepromatous) patients. In the present study, an attempt was made to immunomodulate the anergized T cells of lepromatous leprosy patients by presenting the mycobacterial antigen in combination with T cell adjuvant, murabutide (active analog of muramyl' dipeptide, MDP-BE) and a Trat peptide (T cell epitope of Integral membrane protein (Trat) from Escherichia coli) in particulate form (liposomes) or soluble form (media). PBMNC of normal, BT/TT and BL/LL were stimulated in vitro with five mycobacterial antigens (Ag) in the following formulations, Ag, Ag+murabutide, Ag+murabutide+Trat peptide either in liposomes or in medium. All the five antigen(s) when delivered in liposomes containing murabutide and Trat peptide showed a very high lymphoproliferative response (p<0.001) in all the three groups. IFN-gamma and IL-2 were significantly (p<0.001) high in these culture supernatants compared to IL-10 and IL-4 confirming a shift from CD4+Th2 to Th1 response in leprosy patients with particulate mode of antigen presentation. Interestingly, PBMNC derived from lepromatous patients also showed consistent T cell proliferation with all the formulations. Further, the mechanism of liposomal processing of antigens was studied using different inhibitors that interfere at different stages of antigen presentation. Results indicate that this study may pave way for an immunotherapeutic approach for reverting the anergic T cells of lepromatous patients to proliferating T cells with the release of Th1 cytokines thereby restoring the CMI response in these patients.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi 110029, India.
authors.forename: K
authors.initials: K
authors.lastname: Sridevi
authors.forename: Neena
authors.initials: N
authors.lastname: Khanna
authors.forename: Vineeta
authors.initials: V
authors.lastname: Chattree
authors.forename: P C
authors.initials: PC
authors.lastname: Pal
authors.forename: W
authors.initials: W
authors.lastname: Haq
authors.forename: D N
authors.initials: DN
authors.lastname: Rao
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D017951:Antigen Presentation / Q000276:immunology; D000942:Antigens, Bacterial / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology; D002473:Cell Wall / Q000737:chemistry / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D017077:Culture Media, Conditioned / Q000737:chemistry; D005976:Glutaral / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D016753:Interleukin-10 / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D007918:Leprosy / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008081:Liposomes; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009166:Mycobacterium leprae / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D012969:Sodium Fluoride / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D017077:Culture Media, Conditioned; D007376:Interleukin-2; D008081:Liposomes; D010455:Peptides; D000643:Ammonium Chloride; D016753:Interleukin-10; D015847:Interleukin-4; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007371:Interferon-gamma; C033575:murabutide; D012969:Sodium Fluoride; D005976:Glutaral