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The National Institute of Immunology (NII)’s primary mandate is to understand and exploit the mechanisms of the immune system using various tools of modern biology in order to pursue creative solutions to a broad range of health problems. The focus of research is on:
- To undertake, aid, promote guide and co-ordinate research of high caliber in basic and applied immunology.
- To carry out research for development for new vaccines and immunological reagents for communicable diseases.
- To develop immunological approaches for regulation of male and female fertility.
- To interact with industry for manufacture of vaccines and immunological reagents.
- To organize postgraduate courses, workshops, seminars, symposia and training programmes of a specialized nature in the field of immunology, vaccine development and related areas.
- To organize training programmes for technicians in immunological methods and related techniques.
- To establish affiliation with recognized universities and institutions of higher learning for the purpose of enabling research scholars to register for postgraduate degrees.
- To serve as a national reference centre for immunology and to provide consultancy services to medical and veterinary institutions, public health agencies and industries in the country.
- To provide and promote effective linkages on a continuing basis between various scientific and research agencies/laboratories and other organizations working in the country in the field of immunology, vaccine development and related areas.
- To collaborate with foreign research institutions, laboratories and other international organizations in fields relevant to the objectives mentioned above.
Infection, Immune Mechanisms and Autoimmunity
Studies on Salmonella -host cell interaction revealed a regulatory mechanism involving induction of Toll-like receptor-ligand (flagellin) synthesis for inflammation and innate immunity during infection by the bacterial pathogen.
In a study on systemic lupus erythematosus (SLE), patients showed that a human monoclonal antibody, generated from an SLE patient, recognizes antigens externalized during the process of apoptosis. It can also mediate a variety of potential pathogenic effects including stimulation of the idiotypic network and increasing the range of molecular targets.
Several Ribozymes (Rzs) and DNA-enzymes (Dzs) were constructed that were specific for HIV-1 Tat and Rev genes. Rzs and Dzs cleaved the Tat/Rev RNA very efficiently, and most of them showed excellent activity under simulated physiological conditions of cleavage.
In a study related to biology of T-lymphocytes, a major role for Hsp90 activity in MHC II-mediated antigen presentation pathways in addition to MHC class I restricted antigen has been revealed. Studies have shown that the frequency of naive T cells capable of responding to a given antigenic stimulus is marginally lower in aged mice as compared to young mice as also the activated T cells are more susceptible to death during the antigen-mediated proliferation phase. Hence, immune responses are short-lived in the aged mice and immune memory is also defective.
Effect of IL4- and IL10- deficiency on B cell differentiation in vivo and in vitro reveals that the that IL4 supports clonal expansion in vivo and that in its absence, both plasma cell generation as well as memory cell generation is compromised. IL10, on the other hand, appears to dampen clonal expansion in vivo. In its absence, enhanced primary antibody responses as well as enhanced memory cell generation are observed early after immunization.Ligation of the TNFR molecules CD27 and CD40 on B cells has been shown to skew B cell differentiation towards the memory pathway.
In a study on vaccine against JEV, replication defective recombinant adenoviruses (RAds) have been constructed that synthesized the pre-membrane and envelope (E) proteins of the virus. Oral immunization of mice with RAdEs generated high titres of JEV antibodies and intramuscular immunization of naïve mice with RAdEs showed complete protection against a lethal dose of JEV given intra-cerebrally.
A study has shown that the size of the polymer particles being used as adjuvant can modulate the immune response. It was noted that the Nano-particles promoted cellular immune response, while micro-particles were good at eliciting a humoral response. Detail antigen processing and presentation by polymeric particles are under investigation.
In a study on inhibition of beta cell autoimmunity in children predisposed to get type I diabetes, T-cells involved in presenting auto-antigens peptides to auto-antigens were designed to inhibit their presentation and hence abrogate self-destruction of beta cells.
Structural, Chemical & Systems Biology
Correlations between the promiscuity of the primary antibody response and conformational flexibility in a germ line antibody were addressed through crystallographic analyses revealing a simple mechanism for expanding the primary antibody repertoire.
New insight into the mechanism of cytokine-mediated regulation of intracellular trafficking demonstrates that cytokine differentially regulates endocytic trafficking by controlling the expression of appropriate Rab GTPase.
Several protease-trans-peptidase enzymes (sortases) from Staphylococcus aureus and S. pneumonia, were expressed to study their structure, mechanism of action and inhibition with a view to develop therapeutic inhibitors.
Studies on biotin biosynthesis pathway, which do not exist in humans, suggests that it can be an attractive target for the development of novel drugs against a number of pathogens. Studies on the characterization of the enzyme 7-keto-8-aminopelargonic acid (KAPA) synthase showed broad substrate stereo-specificity in M. tuberculosis KAPA synthase. It sets the stage for inhibitor design.
Another study provides a new possibility that iron can potentate protozoan parasite (Leishmania) death induced by metalloids like arsenic and antimony.
Continuing studies on M. tuberculosis have resulted in identification of a new gene cluster which is required for iron acquisition. Since iron plays a key role in the development of infectious diseases, the biosynthetic pathways that have been studied with the functioning of gene cluster, represent an attractive target for developing an anti-bacterial. M. tuberculosis require mycobactins (membrane associated siderophores) for acquiring intracellular iron so as to adapt to it’s intracellular habitat.
Genetics, Cellular Signalling & Cancer Biology
Study has revealed a novel signaling pathway involving PfPKB, a protein kinase B-like enzyme from Plasmodium falciparum wherein calcium/calmodulin works as the upstream activator suggesting probable intercepting pathways.
Studies related to SPAG9 expression and immuno-genicity in epithelial ovary cancer patients (EOC) shows that majority of epithelial ovary cancer tissues exhibited SPAG9 expression at both mRNA and protein level. The study further indicates that SPAG9 is highly expressed in EOC and is immunogenic in patients.
Work on BLM helicase in the Bloom Syndrome (BS) patients who are predisposed to almost all types of cancers has indicated that it may act in two different stages of the transmission of DNA damage signal during replication. It is thus possible such proteins can have physiological functions different than that are presently ascribed to them.
Studies on the genomics of human Y chromosome in patients with sex chromosome related anomalies (SCRA) and males exposed to natural background radiations (NBR) revealed AZFc somatic micro-deletions and copy number polymorphism of the DAZ genes.
Reproduction & Development
Studies on understanding the molecular basis of fertilization in humans have demonstrated that C-terminal fragment of human ZP3- the primary sperm receptor, is able to induce acrosomal exocytosis in capacitated human spermatozoa. Deletion-recombinant fragments made and being investigated for sperm receptor activity are expected to help in developing drugable novel contraceptive molecules. Multiplex PCR has been designed and validated to screen Y chromosome micro-deletions in infertile oligospermic/azoospermic men,
Study on engraftment potential of murine bone marrow stem cells cultured on three-dimensional matrix in vitro and in vivo showed that both short-term and long-term hematopoietic stem cell compartments could be expanded in reconstituted bone marrow culture environment. The cultured cells were multi-lineage engraftable in a compatible host for more than 8 months. The results suggest that stemness and engraftibility of hematopoietic stem cells do not compromise with their expansion in marrow-like culture environment.
Mechanistic analysis for trans-differentiation of hematopoietic stem cells (HSC) into hepatocytes in hemophilia mice model revealed that a major fraction of Lin- BM (bone marrow) cells differentiate into albumin expressing hepatocytes and express liver specific enzymes, e.g. TAT and TDO in vitro. In vivo studies have shown that in response to liver damage, Lin-Sca-1+ cells multiply in BM and then mobilized in the peripheral blood for migration in the damaged liver. One year in vivo study showed that a significant number of hematopoietic cells differentiate into hepatocytes, expressing albumin and CK-18. BM derived hepatocytes do not express AFP and GGT, markers for liver carcinogenesis. It appears that transformation of BM-hematopoietic cells into hepatocytes is the result of direct differentiation.
Publications, Patents and Technology Transfer
Infrastructure
- A dedicated `state-of-the-art’ laboratory has been set up for carrying out studies and clinical trials on Rotavirus vaccine with PATH
- Innovative designs /specifications have been made for setting up four ‘state-of-the- art’ P-3 facilities
- High-resolution 700 MHz NMR is being set up for implementing NII’s ‘outreach initiatives’ program on “Probing interactions between P. falciparum ACP enzymes of Fatty Acid Biosynthesis by solution NMR”
Publications, Patents and Technology Transfer
- During the year more than 50 peer reviewed manuscripts and 5 reviews have been published.
- During the period, MOA have been signed with two pharmaceutical industries for initiating technology transfer of research leads in the Institute. A technology relating to novel molecules which inhibit Mycobacterial FadD proteins having the potential to be developed as anti-mycobacterial drugs is being explored under a MoU with Astra Zeneca India, Bangalore, and Cadila, Ahmedabad (2006).
Several Patents have been filed in India and Abroad
In India
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- Novel inhibitor of Plasmodium Protein Kinase B and Process thereof
- Novel Bio-conjugates as therapeutic agent and synthesis thereof
- Novel anti-bacterial agents
- Synergistic composition for modulating activity of substrate analogs for NAD+, NADP+, NADH+ or NADPH dependent enzymes and process thereof
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Abroad
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- Novel nucleotide sequences
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During the year, 32 new PhD students have been and 20 summer students of various Universities and colleges provided summer training.
Collaborations
- Inter-institutional networks on research on M.tuberculosis have been set up between NII , NCCS and CDFD.
- Inter-institutional network on research on inhibitors of aggregation and their utility for neurodegenerative disorders has been established with JNU
- Collaboration with DUSC on “Design and evaluation of nanoparticle based targeted drug delivery system” stated
- Inter-institutional network for probing interactions between P. falciparum ACP and Enzymes of Fatty Acids started with IISc., Bangalore
- A Cancer Research Program involving a network of international as well as national collaboration is being initiated between NII and the Centre for Cancer Research and Cell Biology at Queen’s University, Belfast
- One core scientist got the prestigious RO1 research grant from NIH, USA
For more Information, Please Visit http://www.nii.res.in/
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