NII, AIIMS, and CEFIPRA: My Collaborations with India

Gérard Charles Paul Chaouat

Gérard Chaouat with Pran Talwar at NII in New Delhi.

I fell in love with India over several years of collaboration with Indian scientists. I usually prefer to live outside the metropolitan bustle. However, being in Delhi was inevitable. I was witness to the slow disappearance of the star-spangled night sky of Delhi. I liked to be in Delhi, especially for her cultural vibrance and landscaped grandeur, but I had my weekend getaways. 

In the early 90s, the remuneration we got paid in Rupees (INR), could not be used outside India. So we had to use it during our visit. I was visiting as French Directeur de Recherches to collaborate with Indian institutions such as the National Institute of Immunology (NII) and All India Institute of Medical Sciences (AIIMS). It was a mandate to stay on the institution campus, so there were a few things that one could spend on. 

I used to take weekend trips, so much so that I visited almost every city in Rajasthan. I went to Kathmandu, Bhaktapur, and took a mountain flight over Sagarmatha. Regardless of my extensive travel in India to get to know the country; Agra, Jaipur, Jaisalmer, and Goa always remained my favorite. 

I had the pleasure of engaging in collaborations with India. Among several projects, two of them were governmental cooperative projects. They were managed by Centre Franco-Indien pour la Promotion de la Recherche Avancée (CEFIPRA). The projects were: Immunoregulation at the maternal-fetal interface and its applications [Project 204-1; April 1990 to March 1994) and cytokines and integrins in successful implantation and parturition [Project 1604-1; April 1998 to April 2001]. There was another project on HIV between 2000 and 2001.

I also participated in the Pasteur Anniversary celebrations and Joint NII-Institut Pasteur Symposium. I spoke at the World Congress of Immunology in Mumbai as a member of the International Union of Immunological Societies. The highlight of this meeting was its venue, The Taj Mahal Palace Hotel. This was 2001. 

There was a meeting on Reproductive Immunology in Delhi in 2009 for which I visited Delhi again along with Silver Jubilee celebrations of CEFIPRA in Chennai. [Silver Jubille report can be accessed here.]

The CEFIPRA projects (204-1, 1604-1) and the HIV project were handled by its then-Director P G S Mony. He visited Paris on several occasions with his colleagues. There was one Mr. Ganguly, who was the treasurer of the institute who often accompanied Mony. I recall Ganguly counting the pack of rupee banknotes upon my arrival. These gentlemen were extremely efficient scientifically and helpful as far as practical details of my first arrival in India were concerned. It was a pity not seeing them in Chennai for the 25th anniversary of CEFIPRA. I remember visiting the institute at Olof Palme Road and then later at the more spaced facility at Lodhi Road in Delhi. 

The first project was conducted in collaboration with Raja Raghupathy. I met him in Banff and then in Edmonton while visiting my fellow researcher Prof. Thomas Wegmann at the University of Alberta. We had proposed that the Immune system was not a threat that required general immunosuppression for a successful pregnancy. In fact, it was useful, if not necessary. This became evident in later studies. It was based on a model of murine-mediated abortion and its correction alloimmunization of the mother to paternal histocompatibility antigens. The cytokines were just beginning to be characterized. In Banff and Paris, we had begun characterization of what was to be termed “immunotrophism” in the fetal-maternal interface.

From that background research, we engaged in further exploration and a joint project began. We were investigating the involvement of cytokines in “immunoregulation at the feto-maternal interface” but also at the systemic level without neglecting an immunosuppressive component. The studies involved visits of Raja Raghupathy to Paris. He was housed at the Cité Universitaire. He was working at U-262 Inserm unit at Maternité Baudelocque. Me and my doctoral student Elisabeth Menu used to work with him extensively. Elisabeth is now Directeur de Recherches-INSERM at CEA, Paris. 

Back in India, my visits involved regular discussions with students and a lot of benchwork. We were greatly facilitated by the fact that we were housed at the NII residence on the campus. Although I was not able to burn my money much with this facility, it allowed me to have discussions with the students from other labs as well. I was particularly thrilled to interact with lab chiefs at NII, especially Prof. Pran Talwar. I was an enthusiastic attendee of the NII seminars. 

Gérard Chaouat in New Delhi in the 90s.

In addition to the characterization of immunosuppressive factors from trophoblasts and choriocarcinoma, we expanded our research further on the involvement of Colony Stimulating Factors (CSF, mostly CSF-1 and GM-CSF). Its main developmental focus was on using the CBA xDBA/2, CBA x BALB/c murine abortion model and its correction by immunization on the newly discovered cytokines at the interface, IL-3, IL-4, IL-10 on one hand, and the other, TNF and interferon-gamma. This research was lead by me with my collaborator Tom Wegmann, and Raj. This work established the concept that pregnancy was a Th2 phenomenon. Amongst the papers published as an outcome of this cooperation, I must mention: IL-10 prevents naturally occurring fetal loss in the CBA x DBA/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFN-tau. Chaouat G, Assal Meliani A, Martal J, Raghupathy R, Elliott JF, Mosmann T, Wegmann TG. J Immunol. 1995 May 1;154(9):4261-8

This paper is seminal, highly, and repeatedly cited. It is considered as one of the foundations of the Th1/Th2 paradigm. It states that Th1 cytokines are dangerous during established pregnancy, and a “successful allopregnancy is a Th2 phenomenon”. Whereas, Th1 immunity is more linked to abortions [Immunodystrophism, T cells, cytokines, and pregnancy failure.   Raghupathy R, Tangri S. Am J Reprod Immunol. 1996 Apr;35(4):291-6.)] and [Th1-type immunity is incompatible with successful pregnancy.  Raghupathy R. Immunol Today. 1997 Oct;18(10):478-82. doi: 10.1016/s0167-5699(97)01127-4]

[For more Read: A & B]

Thanks to this work, I made several reviews of the subject and traveled worldwide to deliver talks. It makes me happy to see the citation of these papers increasing as fast as one-two per week. 

We worked on the immune abortion model in Delhi as well as in Paris. My collaborator Shabnam Tangri (She is now the Vice President at BioPharma Division of Navigate Biopharma services Inc, -Novartis) worked on cytokines in the placenta for aborting CBA/J mice (mated with DBA/2 males) and non-aborting ones (mated with BALB/c mice or pre-immunized against BALB/c lymphocytes prior to mating with DBA/2 males called the vaccination against abortion model). We had already noticed different abortion rates between Paris, Nice, and Hamilton (Ontario, Canada), but we were struck by extremely high rates of abortion and uteroplacental TNF levels in Delhi. [Expression of cytokines in placentas of mice undergoing immunologically mediated spontaneous fetal resorptions. Tangri S, Raghupathy R. Biol Reprod. 1993 Oct;49(4):850-6.]

This prompted us to test abortion rates in a germ-free environment, and surprisingly the abortion rate dropped exponentially, to be almost null. Only a few meiosis-related genetic anomalies were exceptions. This led us to test the effects of per os (orally administered) antibiotics on abortion rates. This led to studies on bacterial flora in the intestine and abortion [Ecology of danger-dependent cytokine-boosted spontaneous abortion in the CBA x DBA/2 mouse model. I. Synergistic effect of LPS and (TNF-alpha + IFN-gamma) on pregnancy loss.  Clark DA, Manuel J, Lee L, Chaouat G, Gorczynski RM, Levy GA & Ecology of danger-dependent cytokine-boosted spontaneous abortion in the CBA x DBA/2 mouse model: II. Fecal LPS levels in colonies with different basal abortion rates. Clark DA, Chaouat G, Banwatt D, Friebe A, Arck PC. Am J Reprod Immunol. 2008 Dec;60(6):529-33)].

These were the first proofs of the role of maternal microbiota in pregnancy and abortion. This project had nine research publications. 

The second project was conducted in collaboration with Prof. Chandana Das at AIIMS in New Delhi. I remembering staying in a small hotel in Safdarjung Enclave (The Dumpy Inn, I think). It was an interesting experience. However, I was mostly staying in AIIMS. 

We sent Sandrine Zourbas to Delhi to work at AIIMS for a month perhaps Marlene Moussa as well. 

Well, on the research front, Das brought delayed implantation embryos to Paris. The research of these embryos resulted in a joint paper of interest [Expression of pro-inflammatory cytokines in mouse blastocysts during implantation: modulation by steroid hormones. Basak S, Dubanchet S, Zourbas S, Chaouat G, Das C. Am J Reprod Immunol. 2002 Jan;47(1):2-11] It was part of the studies that showed that Th1 cytokines were not a danger at implantation, but in fact, implantation was an inflammatory phenomenon, such as abcedation. The injection of non-self products (spermatozoa and lymphocytes) leads to a high macrophage influx. Its an expression of adhesion molecules, mostly but not exclusive integrins and concomitant integrin expression on blastocyst, needed for adhesion of the embryo in the pre and peri-implantation phases.

We began this project to investigate other cytokines in pregnancy. We started with IL-12, IL-15, and IL-17. It gave rise to the revision of the role of cytokines, even in established pregnancy [A brief review of recent data on some cytokine expressions at the materno-foetal interface which might challenge the classical Th1/Th2 dichotomy.  Chaouat G, Zourbas S, Ostojic S, Lappree-Delage G, Dubanchet S, Ledee N, Martal J. J Reprod Immunol. 2002 Jan;53(1-2):241-56]. 

This paper, albeit not a joint one also became a citation classic. Read more here: [Follicular fluid concentration of leukaemia inhibitory factor is decreased among women with polycystic ovarian syndrome during assisted reproduction cycles. Lédée-Bataille N, Laprée-Delage G, Taupin JL, Dubanchet S, Taieb J, Moreau JF, Chaouat G. Hum Reprod. 2001 Oct;16(10):2073-8. and  Cytokine-dependent abortion in CBA x DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase  David A. Clark, Gerard Chaouat, Petra C. Arck, Hans Willi Mittruecker and Gary A. Levy, J Immunol January 15, 1998, 160 (2) 545-549]. This project was very well received and was a success. 

An interview by Pranav Sharma