• Volume 22, Issue 1

      March 1997,   pages  3-116

    • Missing self by heterogeneous natural killer cells

      Rajiv K Saxena

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      Some murine (YAC, P815 and SP20) and human (Molt4, Raji and HR7) tumour cell lines were (i) treated with IFN-γ for inducing enhanced expression of MHC class I antigen, or (ii) given a brief treatment with citrate buffer (pH 3.0), which resulted in denaturation of class I MHC antigens on these tumour cells. IFL-γ or acid treated tumour cells were used as unlabelled competing targets in cold target inhibition assays. The results indicated that the competing ability of acid-treated tumour cells remained unaltered, whereas IFN-γ treated tumour cells competed with significantly less efficiency. These results have been evaluated in light of the current view of NK cell development and the expression of inhibitory receptors for MHC class I molecules (IRMs), on NK cells. A modified view on NK cell heterogeneity based upon IRM expression has been proposed which reconciles several apparently discordant observations about the activity and role of NK cells. Two classes of NK cells have been proposed. Type I NK ceils have target recognition receptors which do not recognize autologous normal cells, lack IRMs, and may participate in first line of defence against transformed cellsin vivo. Type II NK cells have target recognition receptors for autologous normal cells and express at least one self-reactive IRM in order to prevent auto-killing. Type II NK cells participate in killing those transformed cells which down-regulate their MHC class I expression in order to escape cytotoxic T-cell surveillance. It is also postulated that mechanism of inverse correlation of target cell MHC class I expression levels and their susceptibility to NK cells, involves interference model of missing self hypothesis for type I NK cells and inhibitory signal model of missing self hypothesis for type II NE cells. Finally, it is proposed that acid treatment of tumour cells enhances their lysis susceptibility by making them additionally susceptible to type II NK cells, rather than enhancing their killing by type I NK cells. This proposition would explain the lack of effect of acid treatment on the competing ability of tumour cells, when target cells are only lysed by type I NE cells.

    • Immunoprophylactic studies on cell wall associated proteins ofMycobacterium tuberculosis H37Ra

      Neelam Dhiman Indu Verma G K Khuller

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      The cell wall protein peptidoglycan complex (CW-PPC) ofMycobacterium tuberculosis H37Ra was isolated through sequential extraction of lipids, carbohydrates and soluble proteins. CW-PPC emulsified in FIA was found to induce significant protection in mice against challenge with LD50 dose ofM. tuberculosis H37Rv. To identify the immunoprotective components of CW-PPC, the proteins in avid association with peptidogican were dissociated by chemical treatment with trifluoromethanesulthonic acid (CF3CO3H): anisole (2:1). Immunoreactivity of total (CW-Pr) as well as its component proteins i.e., 71, 60 and 45 kDa proteins of cell wall was studied in animals immunized with CW-Pr-FIA. The 71 kDa protein was found to be most immunoreactive giving higher T-cell sensitization and humoral responses. Further, immunization of mice with 71 kDa-FIA demonstrated enhanced T- and B- cell responses. Mice immunized with 71 kDa-FIA gave significantly higher protection (P ≤ 0.05) against intravenous challenge with LD50 dose ofM. tuberculosis H37Rv, than BCG immunized animals. The results indicate the potential of 71 kDa cell wall protein as a suitable candidate for Cthe subunit vaccine.

    • Mechanisms involved in natural killer cell mediated target cell death leading to spontaneous tumour regression

      Ashok Khar

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      We have studied the mechanisms involved in the spontaneous regression of a rat histiocytoma in syngeneic hosts and tumour cell death processes. In addition to the natural killer (NK) cells which act through antibody dependent cellular cytotoxicity (ADCC), TNF-α also participates in the induction of necrosis in tumours. We have shown that the tumour cell is killed by necrosis which is perforce mediated, and apoptosis leading to target cell DNA fragmentation. A prior activation of the effector cells is essential before it can kill the target cell, as naive effector cells are ineffective. Activation of effector cells is mediated by Thl type of cytokinesin viro andin vivo. IFN-γ seems to play an important role in tumour regression as injection of antibodies to IFN-γin vivo inhibited tumour rejection.

    • In vivo clearance of Japanese encephalitis virus by adoptively transferred virus specific cytotoxic T lymphocytes

      A Desai K Murali-Krishna B Ramireddy V Ravi R Manjunath

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      Japanese encephalitis virus (JEV) is a positive stranded RNA virus that belongs to the flavivirus group. JEV infection damages the central nervous system (CNS) and is one of the main causative agents of acute encephalitis. H-2 restricted virus-specific cytotoxic T lymphocytes (CTL) have been generated specifically against JEV in our laboratory and these CTL have been shown to protect mice against lethal challenge with JEV. Virus replication was found to be inhibited in the brains of animals that were adoptively transferred with JEV specific CTL as revealed by immunohistological staining as well as viral plaque assays. We further show that virus specific CTL could be recovered from such protected mice as long as 45 days after adoptive transfer.

    • Major histocompatibility complex restriction in tuberculosis susceptibility

      R M Pitchappan J N Agrewala V Dheenadhayalan J Ivanyi

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      More than one mechanism may contribute to disease susceptibility in tuberculosis, viz., major histocompatability complex (MHC) restriction phenomenon, spectrum of immune reactivity/cytokine profile and epidemiology induced anergy. Experiments from our laboratories revealed that (i) human leucocyte antigen D-related allele 2 (HLA DR2) predispose for a more severe form of pulmonary tuberculosis encoding a high responder status, (ii) spectrum of immune reactivity to mycobacteria is ‘innate’, and it is demonstrable in healthy individuals from endemic area, (iii) there is no correlation between the purified protein derivative (PPD) response and peptide responses, (iv) once a person is high responder to P16 and P38 derived peptides (6/22), he/she (whether a patient or control) is a high responder for a wide range of mycobacterial peptides and (v)majority of the T-cell clones generatedin vitro, to peptide 16.3 (amino acids 21–40) of 16 kA a mycobacterial antigen, in an HLA DR2 positive healthy individual is HLA DR restricted, permissive and of Th1 phenotype. The results suggested that MHC class II restriction play a role in peptide recognition and the immune response. Nonetheless the outcome and specificity of the immune reactivity and the resultant disease pathogenesis may depend on the promiscuity of peptide recognition and cytokine profiles.

    • Generation of human class I major histocompatibility complex activating factor in serum free medium and its partial characterization

      Aparna Raval Niti Ipuri R K Saxena

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      Human peripheral blood mononuclear cells (PBMCs) activated with Con-A release a soluble factor which augments the expression of class I major histocompatibility complex (MHC) antigens by a variety of tumour cells. Previous attempts to purify this factor called MHC-activating factor (AF) (MHC-AF) made us realize that the presence of large numbers and quantities of irrelevant fetal calf serum proteins in the culture supernatants of the activated human PBMCs, interfered with the purification procedure. It was therefore necessary to standardize the use of a serum free culture medium to generate human MHC-AF. In the present communication we have tried several types of culture media and have identified DCCM-2 as the most suitable culture medium to generate human MHC-AF. MHC-AF generated in DCCM-2 medium appears to be a protein molecule resistant to pH 2 treatment but sensitive to heat treatment (56°C × 45 min) and treatment with proteolytic enzymes trypsin and chymotrypsin.

    • A new 85 kDa, breast tumour associated antigen — A potential diagnostic and prognostic agent

      Utpala Chattopadhyay Saumitra Pal

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      In an attempt to develop measures for early diagnosis and prognosis of the disease and to explore association of murine mammary tumour virus (MuMTV) or related virus in breast cancer, we purified a breast tumour associated antigen (BTAA) from the breast tumour tissues of untreated female cancer patients. The BTAA purified by DEAE discontinuous column chromatography followed by SE-HPLC was an 85 kDa glycoprotein. A high level of circulating antibodies against this antigen was observed, using ELISA, in all the untreated female breast cancer patients. The BTAA was not immunologically related to MuMTV antigens but strongly resembled an 83 kDa glycoprotein tumour associated antigen, purified from MuMTV induced mouse mammary tumour. In patients after surgical removal of the breast tumour, the circulating antibodies to the BTAA decreased gradually, but reappeared in the patients with secondary metastasis. In healthy age matched women or in female patients with carcinoma of tissues other than breast, no significant titre of the BTAA antibodies was observed.

    • Changing of Val47 to Asp47 or to Lys47 enhances the immunomodulatory activity of the human Interleukin-l peptide 47–55

      M Bruhaspathy S K Kar

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      The 47–55 domain of the maturehumanInterleukin-was predicted to be exposed by our computational analysis and confirmed to be so by comparing with X-ray crystallographic as well as nuclear magnetic resonance (NMR) spectroscopic data. Four peptides representing fully or part of this domain with sequences 47–55, 41–61, 45–61 and 50–66 were synthesized and tested for their ability to modulate in vivo, the humoral immune response of Balb/c mice to Shigella dysenteriae 116 kDa antigen(s). The smallest immunomodulatory peptide amongst them was found to be the nonapeptide 47–55. To ascertain the structure-function relationships of this 47–55 peptide, various mutant peptides were synthesized and tested for IL-1β2 like activity in vivo. Change of Val47 to Asp47 or to Lys47 enhanced its immunomodulatory activity significantly while the change of Gly49 to Asp49 or Glu50 to Ile50 or Asp54 to Ile54 had no such effect. The peptides 47–55 and its mutants were first tested for their ability to elicit inflammatory response like PGE2 synthesis by a sensitive radioimmunoassay. The peptides which did not have any inflammatory activity were then tested for their ability to stimulate antigen primed T-cells in vitro in the presence of sub-optimal concentration of the antigen.

    • Immunoprophylactic studies with a 43 kDa human circulating filarial antigen and a cross reactive 120 kDaBrugia malayi sodium dodecyl sulphate soluble antigen in filariasis

      V Chenthamarakshan K Cheirmaraj M V R Reddy B C Harinath

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      Bancroftian filariasis is a major public health problem affecting about 120 million people all over the world. Immunoprophylaxis may serve as an additional adjunct along with chemotherapy and anti larval measures for successful filaria control. Circulating filarial antigen fraction (CFA2-6) containing 43 kDa antigen and adultBrugia malayi sodium dodecyl sulphate (S DS) soluble antigen fraction BmA-2 with a 120 kDa molecule were earlier shown to be reactive with endemic normal sera by immunoblotting and indirect ELISA techniques. BmA-2 was found to be highly cross reactive with CFA2-6. Sera raised against both the antigen fractions showed about 90 % cytotoxicity to the parasites in the presence of jird peritoneal cells inin vitro as well as byin situ micropore chamber implantation technique. Further inin vivo studies using animal model, jirds CFA2-6 and BmA-2 could induce about 90% protection to infection in immunized animals. In passive transfer studies of immunity it has been observed that BmA-2 induced protection is mainly antibody mediated.

    • Flowcytometric assessment of intracellular interferon -γ production in human CD4 + ve T-cells on mycobacterial antigen stimulation

      S Bhattacharyya S N Das A B Dey K Nagarkar J Lobo S K Kapoor H K Prasad

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      Interferon-(IFN-γ) has been considered to be a critical protective immunomodulatory component againstMycobacterium tuberculosis (M. tb.) infection. In this study T-cell proliferation and IFN-γ production upon stimulation with M. tb. were assessed in patients of pulmonary tuberculosis and healthy contacts. The studies were based on lymphocyte transformation test and detection of intracellular IFN-γ production by CD4 + ve T-cells by flowcytometry. Patients showed lower levels of proliferation, the stimulation index being in the range of 2.17 1.1 (mean + SD) compared to the contacts (SI = 4 59±1.6) (P < 0.01). The kinetics of intracellular induction of IFN-γ on M. tb. stimulation showed a proportional increase in the CD4 + ve T-cell population. The increase was maximal between 96–120 h of culture. In healthy contacts the number of IFN-γ expressing CD + ve T-cells increased to 2.5 to 41 × 104 cells/ml in M. tb. stimulated cultures compared to control cultures (0.1 – 15 × 104). In contrast patients showed no/marginal increase in CD4 + ve T-cell population expressing intracellular IFN-γ Thus the lack of induction of IFN in CD4 + ve T-cells in patients could be a critical shortcoming in their ability to combat tubercle bacilli infection.

    • Efforts in diagnosing early leprosy using serological techniques

      Om Parkash M K Beuria B K Girdhar K Katoch U Sengupta

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      Skin scrapings obtained from the lesions of leprosy patients of all types showed 96 % positivity to the serum antibody competition test using monoclonal antibody (ML04)to 35 kDa antigen ofMycobacterium leprae. Further, in vitro culture of full thickness skin biopsies from lepromatous patients were noted to release IgG antibodies toM. leprae with a peak antibody response at 48 h. The significance of this local antibody response toM. leprae in skin has been discussed for its possible use in diagnosing early leprosy.

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