Breakthroughs and challenges

The Tenth International Congress of Immunology, held in New Delhi, provided a forum to assess the trends and directions in immunology research, but the deliberations are unlikely to have an impact on ongoing indigenous research in the field despite its importance to national health care.

R. RAMACHANDRAN
in New Delhi

PICTURES: RAJEEV BHATT

HOSTING a major international scientific meeting in India at considerable cost makes objective sense if there exist a critical mass of scientists working in the given discipline in the country to benefit from it. Immunology, the area of biological science concerned with the innate or acquired resistance in higher living forms to infections by micro-organisms, is, however, not a field where holding a mega international conference, such as the week-long Tenth International Congress of Immunology (ICI) which concluded on November 6, could be unequivocally justified.

The lack of sufficient expertise in India is particularly glaring when one looks at modern immunology after the advent of genetic engineering methods and biotechnology. Acquiring high levels of such expertise requires expensive infrastructure, equipment and instrumentation, and most laboratories in India, particularly in the universities, do not have the funds for investment in these. As a result, the general level of research has not been good enough to keep pace with the rapid advances made in the techniques of molecular characterisation of pathogens and in the understanding of the molecular biology of the immune system. The fact that the molecular characterisation of the Indian human immunodeficiency virus (HIV) strain - the so-called C-subtype - is yet to be done despite a major research initiative and funding on this front provides further evidence of this.

This is not to deny the existence in the country of a fair number of scientists of high calibre, who are engaged in the study of the basic biology of immunology and vaccines. However, on the whole, the science of immunology in India is far from having evolved into a comprehensive discipline with appropriate linkages with the medical community, clinical immunological studies and the industry to have any impact on public health. Until such evolution is complete, its pursuit will remain restricted to select academic institutes and a handful of scientists. The relevance then of the ICI, which was attended by over 2,500 scientists, mostly from the West (some of them were non-resident Indians), becomes questionable because of the limited impact that the deliberations are likely to have on ongoing indigenous research in the field despite its apparent importance to national health care.

President K.R. Narayanan, Union Minister for Human Resource Development Murli Manohar Joshi, former Director of the National Institute of Immunology G.P. Talwar and Prof. Tomio Tada at the Tenth International Congress of Immunology in New Delhi.

Dr. Satyajit Rath, a senior scientist at the National Institute of Immunology (NII), New Delhi, said:"From the perspective of scientists working in the field, you do not get much beyond what is already there in published literature. Nowadays, for whatever reasons, top scientists of the world rarely present the latest data in such huge conferences. They usually are presented in small focussed meetings where there is an exchange of ideas and opinion at a different intellectual level." A Professor of biotechnology at the Jawaharlal Nehru University said: "The Rs.80 lakhs spent by the Government on the congress would have been better spent if invested to improve infrastructure in the universities."

The congress left much to be desired in terms of organisation and management. Various factors, including the nuclear tests in May, seem to have contributed to this. Apparently in response to the nuclear tests, there was also a move by the American Immunological Society to boycott the congress. Although there was no formal boycott, the move seems to have had an impact on the level of U.S. participation.

"Conference programmes were being constantly changed until the last moment and I did not even know when my talk was scheduled," said Dr. B. Subba Rao of the University of Kentucky. Many scientists felt that the workshops on specialised topics were poorly organised and this affected their content as well as response particularly from the student community.

A protest was organised outside the venue of the congress on the inaugural day by women activists against research on immuno-contraception and the development of antifertility vaccines, which brought into focus an ethical issue of relevance to India where substantial work is done in this area.

A section of the participants.

For the media too, given the highly specialised and technical nature of the meeting, the conference was unsatisfactorily organised. There were no press releases or briefings; nor was there any facilitation to meet visiting scientists. Any fruitful exchange, such as the impromptu press conference by Dr. Anthony Fauci, the AIDS (Acquired Immune Deficiency Syndrome) expert from the National Institutes of Health (NIH), U.S., who gave a plenary lecture on the last day, was purely a matter of chance.

Prof. G.P. Talwar, former NII Director and the president of the 10th ICI, however, thought that the event was a great success. "It was way beyond my expectations. We had very good participation from the U.S., the United Kingdom, Japan, Europe as well as China, Russia and, of course, India. Real top scientists came and there was general appreciation for the organisation, and the quality of science was very high," he said. "The revenue generated by way of registration fee and sponsorship in foreign exchange is far greater than the money spent, not to speak of the indirect benefits of tourism," he added.

NOTWITHSTANDING the shortcomings, the congress provided a forum for scientists to discuss the findings of research made since the last congress. For the non-specialist, it gave a fair idea where advanced research in immunology lay. On the applied side, as Dr. G.J.V. Nossal of the University of Melbourne put it, "There is genuine renaissance in vaccinology: molecular vaccines, mucosal vaccines, a wide variety of injectible and mucosal adjuvants (substances which enhance the vaccine action), micro-encapsulated vaccines, even edible vaccines (transgenic plants and fruits which carry the gene for the antigen) and, arguably the most powerful development of all, the DNA (deoxyribonucleic acid) vaccines (see box). It is a surfeit of riches. But alongside there is a new realism. There are infections like the big three - HIV/AIDS, malaria and tuberculosis (TB) - and diseases like cancer, allergies and autoimmune disorders such as diabetes, rheumatoid arthritis, multiple sclerosis, where we do not understand how the immune system works. The body does not develop full immunity as in the case of measles or small pox. Scientists have to do better than nature, be cleverer than the pathogen. This really rotates around how to activate the T-cells (the thymus-linked white blood cell component of the immune system)."

Therein lies one of the outstanding issues of immunology today: what are the signals to which the immune system responds? As one knows, the immediate immune response is to fight the pathogen with antibodies, which bind to the antigens and neutralise them. Then there is memory or latent response, which is T-cell mediated. When and how does the immune system decide to switch off one and switch on the other? In the last three years there has been increasing understanding of the fact that these two pathways are substantially mutually exclusive. Now there is also a substantial understanding of these two qualitatively different pathways.

Dr. Nossal said: "The role of cytokines, the messenger molecules from lymphocytes and macrophages, and the cytokine-balance in guiding the immune response and the cytokine receptors which transcript the series of signals, are now being better understood." This gives rise to the question: what is the higher level regulatory structure and how does this immune regulation control these two pathways with the aid of cytokines? Another question, from the perspective of infections, is on the pathway by which each infectious disease presents itself to the host immune system in a distinctly different manner. A major component of current research activity is the detailed determination of the biochemical pathway by which the infection attacks the immune system in order to enable better interruption of the infection by chemotherapy. HIV infection is a classic example of this approach, and for diseases where a potential vaccine is not in sight, such very specific chemotherapeutic intervention may hold promise.

The third outstanding issue is the evaluation of the non-specific component of the immune system. That is, until recently the antigen-antibody interaction was assumed to be highly specific and this specificity further drove the immunity at the cellular level. Of late scientists have increasingly realised that the intereactions at the primary level in the cells known as the antigen presenting cells (APCs) - dendritic cells, macrophages, eosonophils and cells on the mucosal surface - seem to exercise a tight control over the immune response of the B-cells (the bone-marrow linked white blood cell component of the immune system, which generates antibodies in response to an invading antigen) and the T-cells. This realisation has also given rise to a new approach to the development of vaccines. For example, there is a kind of revival in the role of mucosal immunology because three-fourths of the immune system exists here and because of this oral vaccines, which first reach the mucosa, are being increasingly investigated. The development of DNA vaccines, which are targeted at dendritic cells of the skin, and the concept of edible vaccines, which encounter the mucosa first, would also exploit the role of the APCs in generating appropriate immune responses.

Nobel laureate Dr. Rolf M. Zinkernagel said in his plenary lecture that the completely successful vaccines had been the vaccines for small pox and measles and the oral vaccines for polio. He added that all the simple vaccines had already been discovered. The challenging diseases are those that evade these first-level responses. An important finding reported by Dr. Zinkernagel related to the role of the amount of antigen and its three-dimensional structure itself in eliciting appropriate B-cell and T-cell responses. His finding in virus-infected mice that "too much antigenic load burns out T-cells, exhausts the T-helper cells (which aid the B-cells to produce antibodies) and that the antigen should reach the T-cells in a staggered fashion for T-cell response" affords an important insight for vaccine design and delivery strategies.

Another important lesson from researches in TB vaccine development is the fact that live vaccines seem to generate cellular immunity. This is because of the presence of secretive antigens in vivo which do not express themselves in vitro or in killed vaccines. For any vaccine strategy, it has to be known which of these secretive antigens can help generate cellular immunity. Given the above uncertainty about the antigen specificity, vaccine design will continue to be based on an empirical approach rather than on rational design using modelling techniques based on molecular structure, according to Dr. M.H.V. Regenmortel of Centre National de la Recherche Scientifique, Strasbourg, France.

The above factors notwithstanding, advances made in protein synthesis have led to an extraordinary amount of peptide and antibody engineering with the aim of eliciting specific B-cell and T-cell responses and arriving at appropriate vaccine design strategies. Dr. J.A. Berzofsky of the National Cancer Research Institute, NIH, U.S., has developed vaccine constructs for HIV infection that alter the antigenic binding sites to bind "more provocatively and effectively" to the T-cells as compared to the binding that takes place using a vaccine based on natural HIV isolates.

Outside the venue of the congress, a demonstration against the anti-infertility vaccine.

As regards other diseases, the biggest action is in the understanding of tumour immunology, regulation of cellular growth and division. Vaccines against some cancers, which are clearly microbial - liver, stomach and cervical - seem fairly straightforward. The basic question that is being asked is in what respect cancer cells differ from normal cells and whether the differences can form the basis of a vaccine. Dr. Fritz Melchers of the Basel Institute of Immunology said:"We now have a full understanding of how the assembly line that manufactures B-cells and T-cells operates beginning with the bone marrow and the thymus respectively. Now we must identify at which point in this assembly line is the deficiency which causes a tumorous growth. Once we know we can identify the genes and intervene accordingly."

Dr. Melchers said that chemotherapy and irradiation are useful only for tumours in cells that divide. "But," he said, "there are the so-called resting cells which do not divide but are potentially disease-inducing and are resistant to chemotherapy and irradiation. The problem is to attack these through different means. You make a specific antibody that recognises a cancer cell and attach a toxin to that antibody so that it goes to the tumour cell like a magic bullet and kills it. The problem is not solved yet." Similar approaches are being pursued for autoimmune disorders.

The congress proceedings have pointed to a sobering thought that despite remarkable breakthroughs made in the science of immunology and vaccinology, there are a host of outstanding issues and poorly understood body mechanisms in the fight between disease and man. "There is a lot to do. That, in fact, is the privilege of being in science. Even though we have a crisis-ridden job at hand, work hard and never ever give up," is the message that Dr. Zinkernagel gave the congress gathering. Hopefully the message has gone down well with the scientists.

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