commentary

Immunology in India: an emerging story

Kanury V S Rao

Although immunological research is of only recent origin in India, it is nevertheless rapidly becoming an area of choice for young researchers in this country.

he perennial appeal of lies Tin the fact that it provides a window for almost every aspect of biological and biomedi- cal research. The plasticity of lymphocytes as

http://www.nature.com/natureimmunology they switch among quiescence, active prolif- eration and various differentiation programs encapsulates the essence of both cell and the gene expression events that drive cell fate ‘decisions’. The structural and functional diversity of -related receptors elicits questions in evolutionary biology, genetics, , biophysics and structural biol- ogy. Although belated, this universe of excit- ing opportunities offered by immunological research is also rapidly being increasingly rec- Nature Publishing Group Group Nature Publishing

8 ognized by researchers in India. And with the present availability of resources and educated 200 manpower, the country is geared to mature © into an important contributor to this field.

A historical perspective The history of medicine in India goes back to Susruta, the father of plastic surgery, is considered the originator of the rhinoplasty technique that remote antiquity, to a period between 4,000 has been practiced since 600 BCE. A detailed description of the procedure is provided in the Susruta and 900 BCE known as the ‘Vedic period’. Samhita. The procedure later spread from India to Persia and Egypt and, many centuries later, to Although early Vedic medicine represented an Europe and is still practiced today by some families in India and Nepal. Reprinted from ref. 18 with amalgamation of religious, magical and empir- permission from the author. ical elements, a more rational approach known as ‘Ayurveda’ (or ‘the art of healing’) gained a from perturbations of this equilibrium. The the human body. It also discusses the etiology, foothold by around 1,000 BCE. Ayurveda Susruta Samhita (the treatise of Susruta) and diagnosis and treatment of several human dis- continues to flourish even today as an alter- the Charaka Samhita (the treatise of Charaka) eases, including autoimmune diseases. native system of medicine. It was founded on represent two important pillars of Ayurveda The roots of modern immunology in India, the principle that the equilibrium among the and were compiled between 800 and 600 however, were established only recently, occur- bodily humors (or ‘Doshas’) defines the overall BCE. The Susruta Samhita provided the first ring through the conversion of a small group of homeostasis of the body, which is reflected in systematic division of surgery into separate biochemists at the All India Institute of Medical the natural immunity of the host. Atopic and fields. The highlight of Susruta’s achievement Sciences (AIIMS) in Delhi. This conversion other chronic diseases, as well as susceptibil- was the operation of rhinoplasty; Susruta is was the direct result of a series of courses in ity to pathogens, were all thought to derive internationally regarded as the father of plastic immunology sponsored by the World Health surgery. The Charaka Samhita, in contrast, rep- Organization and organized by G.P. Talwar Kanury V.S. Rao is with the Immunology Group of resents a treatise on medicine. It deals in elabo- in the biochemistry department, first held in the International Centre for Genetic Engineering rate detail with subjects such as fetal generation 1968. The consequent exposure to the work and Biotechnology, New Delhi 110067, India. and development, the anatomy of the human of leading international experts in the field e-mail: [email protected] body, and the function and malfunction of prompted several of the participants to enter

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this unfamiliar but exciting area. Research not ‘new’ proteins but instead represented research in various aspects of biology, includ- programs founded on immunology-oriented post-translationally modified isoforms of well- ing immunology. themes soon materialized. These themes known ‘housekeeping’ gene products4. Education has always occupied a preeminent included the development of contraceptive Studies of the thresholds that regulate acti- place in Indian history, and the earliest known vaccines (G.P. Talwar), major histocompat- vation versus anergy and proliferation versus universities of Nalanda and Taxila flourished ibility complex (MHC) polymorphism (M.C. differentiation of T cells were jointly initiated here as far back as in the fifth century BCE. Vaidya) and an examination of immune by Satyajit Rath and Vineeta Bal at the NII. So To reexamine the educational requirements responses in patients with leprosy (G.P. Talwar far, several previously unknown pathways have of an independent India, however, the Indian and Indira Nath). Although the early phase of been delineated; examples of these include the government set up a University Education the leprosy program concentrated on humoral function of protein kinase A in mediating the Commission in 1948. The report of this responses1, Nath subsequently expanded its commitment of activated T cells to second- committee led to the establishment of the scope to include a detailed study of cell-me- ary responsiveness, as well as the function University Grants Commission in 1953. This diated immunity2. Her work showed that the of inducible nitric oxide synthase in regulat- commission was charged with the mandate of generalized immune suppression in Indian ing T cell death and immune memory5,6. My promoting and coordinating university educa- patients was due to the secretion of soluble group at the International Centre for Genetic tion and research in India; so far, there are over factors such as leukotrienes, prostaglandins Engineering and Biotechnology (ICGEB) in 230 universities spread across the country. In and interleukin 10 by monocytes. In a similar Delhi has pursued studies of antigen recog- addition, the Indian government has recently vein, N.K. Mehra augmented the program on nition by primary B lymphocytes and their announced the creation of thirty new central HLA polymorphisms at AIIMS, and the HLA- subsequent activation and differentiation in universities, five new Indian institutes of sci- specific associations now being investigated T cell–dependent responses. A highlight of ence education and research, eight new Indian range from transplantation to susceptibility to this research has been the identification of a institutes of technology and twenty new insti- many infectious and chronic diseases. Notably, previously unknown subset of receptors for tutes of information technology. nuclei for immunological research also began immunoglobulin D on primary cells and the Research in India is also actively pursued

http://www.nature.com/natureimmunology to emerge in other parts of the country during elucidation of their function in defining anti- in national research and development insti- this period. Thus, R.S. Kamat at the Haffkine gen-affinity thresholds for memory B cell dif- tutions. These institutes, such as the Council Institute in Bombay began to look at immune ferentiation7. of Scientific and Industrial Research, are sup- responses generated against bacterial infections, The Indian Immunology Society was ported by various governmental branches. whereas V.R. Muthukkaruppan and colleagues established in 1971 and began to hold annual Another organizational structure for health-re- at the Madurai Kamaraj University added fur- meetings in 1973. It now boasts about 1,000 lated research is the Indian Council of Medical ther strength to the leprosy program. registered members and has recently launched Research (ICMR), formed in 1949 and funded The growing interest in immunology soon new initiatives to increase active participation by the Ministry of Health. The ICMR directly led to the establishment of the National from its student community. To promote the supports over 25 research institutes in the coun- Institute of Immunology (NII) in Delhi in exchange of ideas, an informal platform known try covering all aspects of biomedical sciences, 1986, with G.P. Talwar as its founding direc- as the ‘Molecular Immunology Forum’ was also including infectious disease, autoimmune dis- Nature Publishing Group Group Nature Publishing

8 tor. At that time, Talwar was at the forefront conceived in 1993. Its membership is restricted ease, oncology, nutrition, epidemiology and of international research aimed at developing to active researchers who meet once a year. The medical statistics. The now-famous Chingleput 200 antifertility vaccines, and his demonstration objective of this forum is to serve as a peer- trials for bacille Calmette-Guerin vaccination, © that β-human chorionic gonadotropin, a self review group for ongoing work so investiga- which first established the principles of dou- antigen, could be used as a contraceptive vac- tors may benefit from this collective input. The ble-blind randomized trials in humans, was cine in women remains a landmark contribu- Molecular Immunology Forum has contrib- conducted by ICMR’s Research tion to the field3. Talwar is also credited with uted considerably toward enhancing the qual- Centre (Chennai). Notably, this study also the first isolation of a new strain of mycobac- ity of Indian research efforts in immunology. highlighted the inadequacy of this vaccine in teria now called ‘Mycobacteria indicus pranii’. A countries in which tuberculosis is endemic8. heat-killed form of this mycobacteria has since Research funding and institutions The ICMR also actively supports projects of proven effective as an adjunct to standard mul- The independence of India from colonial rule scientists working in other institutions and tidrug therapy for patients with leprosy and is in late 1947 saw the emergence of a national universities through its extramural program. commercially available as an immunothera- mindset that was determined to be self-reliant. Research in clinical, basic and ‘translational’ peutic vaccine formulation. A natural outcome of this was an emphasis on aspects of immunology in various laboratories Research into the more basic aspects of strengthening indigenous abilities in science has received strong support from the ICMR. immunology began to gain ground by the late and technology. India’s first prime minister, To further accelerate the growth of science, the 1980s. This was initiated by a small group of Jawaharlal Nehru, also visualized science as a Ministry of Science and Technology established young researchers who had recently returned vehicle for qualitatively transforming a society the Department of Science and Technology in from postdoctoral stints abroad. G.C. Mishra still rooted mostly in tradition. The Council 1971 to support basic and applied research in at the Institute of Microbial Technology in of Scientific and Industrial Research was one the various institutions and universities in the Chandigarh began his career by exploring of the first institutional structures to be set up country. the still relatively new phenomenon of T cell with the mission of promoting scientific and But perhaps the strongest stimulus for reju- costimulation. The novel approach adopted industrial research and development. This venating research in the life sciences came with by his group led to the identification of an council functions under the auspices of the the setting up of a separate Department of entirely new class of costimulatory molecules Ministry of Science and Technology and has Biotechnology (DBT) in the Ministry of Science that selectively induced T helper type 1 or type grown over the years to its present tally of over and Technology in 1986 to actively promote 2 differentiation. Notably, these molecules were 38 research institutions, 11 of which focus on the field of modern biology in India. Since its

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since evolved. Lymphocyte activation and dif- ferentiation and the associated processes of antigen presentation and costimulation repre- sent key areas of interest to immunologists in India. Collaborative efforts among the groups of Anna George, V. Bal and S. Rath (NII) have identified many important mechanisms involved in regulating the activation-apopto- sis balance in T cells, as well as in the differen- tiation of T cells into effector versus memory populations. Their studies of antigen presen- tation pathways have led to the identification adhuri Thakar adhuri M of a previously unknown pathway in which cytoplasmic proteins processed by the protea- Learning under the Bodhi tree. Students debate the merits of the hygiene hypothesis at a recent annual some are then transported to the endo-lyso- meeting of the IIS. Such open-air sessions, which provide an opportunity for students to engage in self-driven debate on important ideas in immunology, is now an integral component of these annual somal compartment for presentation by MHC 9 meetings. Another such initiative of the IIS is the annual publication of a student newsletter. Both class II molecules . Samit Chattopadhyay at the contributing authors and the editorial board of this newsletter are exclusively PhD students and the National Centre for Cell Science (NCCS) postdoctoral fellows. Photograph courtesy of Madhuri Thakar, National AIDS Research Institute, . in Pune has shown that transcriptional activa- tion of the transcription factor T-bet during creation, the DBT has contributed considerably 1990s that led to a healthy national growth T helper type 1 differentiation is regulated by to the growth of biology research; it has achieved rate of between 8% and 9% in the past decade, the matrix attachment region–binding pro- this, at one level, through the generous funding however, has reenergized the scientific ambi- tein SMAR1, whereas from

http://www.nature.com/natureimmunology of projects in individual laboratories. In addi- tions of the country. A substantial increase the same institute is exploring the function tion, the DBT has also been actively involved in in science funding by the Indian government of another MAR-binding protein, SATB1, in establishing new institutes and upgrading the (for example, the budget allocation for DBT regulating gene expression from the MHC infrastructure of existing ones. The NII rep- has increased by about fourfold over the past class I locus. Others groups studying various resents the first new institute to be established 5 years) has led to aggressive investment in facets of T cell activation, death and differen- by the DBT, and at least seven more institutes new institutions and universities, upgrading tiation include those of G.C. Mishra (NCCS), focusing on broad areas such as , of infrastructure, new research programs of (National Centre for Biological infectious disease biology, brain research, plant an interdisciplinary nature and much greater Sciences, Bangalore), Dipankar Nandi (Indian biotechnology, and biodiversity have funding for individual projects. In addition, Institute of Science, Bangalore), Satish Devdas been added to the DBT’s portfolio. several attractive programs have also been ini- (Institute of Life Sciences, Bhubhaneswar) Extramural funding of research by the DBT tiated to induce scientists of Indian origin who and Gobardhan Das (ICGEB). Nature Publishing Group Group Nature Publishing

8 is mediated by several expert committees of are working abroad to return to India. A good In addition to studies of T cells, the acti- peers, called ‘task forces’, that review and fund example is the joint initiative between the DBT vation and differentiation of B lymphocytes 200 project proposals in specific areas of expertise. and the Wellcome Trust to offer 70 fellowships is another area from which substantial con- © Although there is not yet a specific task force annually for biomedical research, at various tributions have emerged. A. George and her for immunology, immunologists can seek levels, for the next 5 years. The cumulative collaborators originally identified CD27 as a funding from those dealing with basic science, effect of all these initiatives on scientific output critical participant in driving the differentia- medical biotechnology, infectious disease biol- is sure to be felt in the coming years. tion of memory B cells10. The present focus ogy, human genetics or animal biotechnology of this group is to delineate the ‘downstream’ or the task force on interdisciplinary research. Present research signaling and gene expression events that are In addition, there are other committees spe- Although unintended, the introduction of involved. My group has identified a previ- cifically set up to promote infrastructure immunology to India through exercises in ously unknown feedback loop that regulates improvements and to review and fund ‘big- vaccine development led to a general percep- the amplification of signaling from the B cell budget’ research programs that involve many tion that immunology was mainly a ‘trans- antigen receptor11, and we are now using collaborating partners. In the current 5-year lation-oriented’ science. New vaccines were systems biology to ‘decode’ the mechanisms plan period, special emphasis is being given the desired end goal, and diagnostic kits were of signal processing to understand how con- to multi-institutional and multidisciplinary considered the ‘low-hanging fruit’ to be picked text-specific cellular responses are achieved. programs, including the active promotion of along the way. The enormous public health In collaboration with the structural biologist collaborative partnerships among academic burden, coupled with the limited resources Dinakar Salunke (NII), we have also addressed laboratories and biotechnology and pharma- available during the formative years of Indian the question of how the germline-encoded ceutical industries. immunology, also contributed to this layper- repertoire of the B cell antigen receptor has Although a strong framework for govern- son’s view. Asking questions about more basic a vast potential for recognizing diverse anti- mental funding of science has emerged in a issues related to the functioning of the immune gens, which is achieved through the structural short time span, the government’s capacity to system was considered less important and, per- plasticity of the antigen-combining site of the galvanize scientific research was initially tem- haps, even socially irresponsible. receptor12. In addition to this, Salunke is also pered by economic constraints. The available Recent years, however, have witnessed a attempting a structural resolution to deter- resources were limited and therefore too thinly ‘sea change’ in this perspective, and several mine why some antigens are allergenic in spread. The economic turnaround in the mid- robust programs on basic immunology have nature. Devender Sehgal’s group at the NII is

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focusing on examining somatic mutation and many previously unknown polymorphic loci tific infrastructure give reason for optimism the affinity maturation of antibody responses has already been identified, the most notable that this will also affect immunology research to model antigens. being the gene encoding transforming growth both by expanding the pool of Indian immu- Although there has been considerable factor-β1 (ref. 16). At the Sanjay Gandhi nologists and by providing them with the state- ‘broadening of the base’ in recent years, infec- Postgraduate Institute of Medical Sciences in of-the-art tools for their research. tious diseases continue to dominate immu- Lucknow, Sonya Nityanand has developed a The paradox of India is that although its nology research in India. G.C. Mishra and his strong program for identifying the mediators cultural identity dates back to the origins of group are examining the involvement of den- of inflammatory responses in Takayasu’s arteri- recorded history, it is still in its infancy in dritic cells in regulating the host response to tis. A group headed by (NCCS) is terms of its identity as an independent and dengue infection, and S. Bandopadhyay (Indian exploring the possibility of manipulating CD40 sovereign nation. India is only now begin- Institute of Chemical Biology, ) is test- signaling to optimize T cell–dependent antitu- ning to emerge as a state with the wherewithal ing the possibility of using antigen-primed mor responses. This strategy is based on his and confidence to chart its own future. The dendritic cells as a vaccination strategy for own earlier finding of a functional dichotomy present availability of economic resources, leishmanaisis. At ICGEB, K. Natarajan and of CD40 whereby it naturally limits antitumor coupled with a firm political commitment Pawan Sharma are investigating the regula- responses by inducing interleukin 10 (ref. 17). to invest for the future in knowledge-based tion of host innate immune responses by the Immune dysfunction in cancer and exploiting arenas also bodes well for the future of secretory antigens of tuberculo- natural killer and γδ T cells for cancer therapy immunology in India. The timing of this is sis. Studies from Natrajan’s group suggest that is the theme of Shubha Chiplunkar’s research particularly fortuitous, as it coincides with these antigens facilitate the creation of a ‘safety (Advanced Centre for Treatment, Research the emergence of India, with close to half a niche’ that allows the pathogen to evade host and Education in Cancer, Mumbai), whereas billion of its people below 30 years of age, as immune responses13. In contrast, H. Krishna researchers at the National Aids Research one of the world’s ‘youngest’ nations. Thus, Prasad and his team at AIIMS are concentrat- Institute in Pune are characterizing innate and the burden of responsibility for fruitfully ing on identifying mycobacterial antigens that adaptive immune responses in both early infec- exploiting ongoing initiatives will be shoul-

http://www.nature.com/natureimmunology are immunogenic in humans. The regulation tion with human immunodeficiency virus and dered by a new generation that is unencum- of host immunity by M. tuberculosis also con- coinfection with human immunodeficiency bered by the trappings of either history or the stitutes the research theme of (Bose virus and tuberculosis. mitigating circumstances experienced by its Institute, Kolkata) and True to its roots, vaccine development con- predecessors. For immunology in India, then, (Centre for DNA Fingerprinting & Diagnostics, tinues to represent a strong component of this could well mean a considerably enlarged ). Basu’s work has provided impor- the immunology research scenario in India. work force asking bolder and more risky, but tant information on the pathogen-mediated A rotavirus vaccine developed at AIIMS by original, research questions. To what extent suppression of innate immune responses in the M.K. Bhan is now undergoing clinical trials, this favorable alignment will eventually ‘trans- host14. Ayub Qadri (NII), studying the regu- whereas the technology for large-scale produc- late’ into scientific leadership ‘on the ground’ lation of inflammatory and innate immune tion of a vaccine for Japanese encephalitis virus is something that only time will tell. responses during infection with pathogenic developed at the NII has been transferred to an

Nature Publishing Group Group Nature Publishing ACKNOWLEDGMENTS

8 salmonella, has shown that the synthesis and Indian biotechnology company. The groups of I thank S. Jamwal for help in gathering the secretion by salmonella of monomeric flagel- V.S. Chauhan and Chetan Chitnis at ICGEB

200 information required for this commentary. lin, a ligand for Toll-like receptor 5, is induced have separately developed candidate vaccines © through the direct sensing by the bacteria of for Plasmodium falciparum and Plasmodium 1. Verma, R.C., Balakrishnan, K., Vasudevan, D.M. & Talwar, G.P. Int. J. Lepr. Other Mycobact. Dis. 39, 20–24 15 host-produced lysophospholipids . Such vivax, respectively. Preparations are underway (1971). host-specified induction of a Toll-like receptor for their phase I clinical trials. Finally, in terms 2. Nath, I. & Singh, R. Clin. Exp. Immunol. 41, 406–414 (1980). ligand by the pathogen represents a previously of new and more potent vaccines for tubercu- 3. Talwar, G.P. et al. Proc. Natl. Acad. Sci. USA 91, 8532– unknown regulatory mechanism for the acti- losis, promising leads are emerging from the 8536 (1994). vation of inflammatory and innate immune laboratories of Anil Tyagi (Delhi University), 4. Vig, M. et al. Mol. Pharmacol. 62, 1471–1478 (2002). responses in the host. Arvind Sahu (NCCS), S. Vijaya (Indian Institute of Science, 5. Prasad, D.V. et al. J. Immunol. 169, 1801–1809 in contrast, is investigating the function of Bangalore) and Javed Agrewala (Institute of (2002). 6. Vig. M. et. al. J. Clin. Invest. 113, 1734–1742 viral complement control proteins in mediat- Microbial Technology). (2004). ing immune evasion. 7. Chaturvedi, A., Sidiqui, Z., Bayiroglu, F. & Rao, K.V.S. Research in clinical immunology has also Future prospects Nat. Immunol. 3, 951–957 (2002). 8. Baily, G.V. Indian J. Med. Res. 72, 1–74 (1980). gained ground in recent years, with a steady It is evident from sampling of ongoing activi- 9. Rajagopal, D., Bal, V., Mayor, S., George, A. & Rath, S. increase in the number of groups working in ties presented here that there has been a gratify- Eur. J. Immunol. 36, 828–841 (2006). this area. At the NII, Rahul Pal is exploring the ing intensification of immunological research 10. Raman, V.S., Akondy, R.S., Rath, S., Bal, V. & George, A. J. Immunol. 171, 5876–5881 (2003). link between antilymphocyte antibodies and in India. Nonetheless, the ‘critical mass’ of 11. Singh, D.K. et al. Cell 121, 281–293 (2005). autoimmunity, whereas Rajni Rani is prob- immunologists continues to be very restrictive, 12. Sethi, D.K., Agarwal, A., Manivel, V., Rao, K.V.S. & Salunke, D.M. Immunity 24, 429–438 (2006). ing the association of diabetes with polymor- limiting the extent of Indian contributions to 13. Salam, N. et al. PLoS One 3, e2869 (2008). phisms in gene loci encoding and the field. Although important discoveries have 14. Pathak, S.K. et al. Nat. Immunol. 8, 610–618 (2007). MHC molecules. A systematic delineation of emanated from Indian immunologists, these 15. Subramanian, N. & Qadri, A. Nat. Immunol. 7, 583–589 (2006). the genetic basis of susceptibility to asthma is have been sporadic in nature. It will be impor- 16. Nagpal, K. et al. J. Allergy Clin. Immunol. 115, 527–533 underway in the laboratory of Balram Ghosh tant to transform these occasional bursts into a (2005). 17. Murugaiyan, G., Martin, S. & Saha, B. Trends Immunol. at the Institute for Genomic and Integrative more steady and sustained steam. The present 28, 467–473 (2007). Biology in Delhi. A strong association with governmental efforts to strengthen the scien- 18. Saraf, A. Internet J. Plastic Surgery 3, 2 (2007).

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