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R Raghupathy

Publications and source records attributed to R Raghupathy.

At least 37 records · Page 2Linked to original sources
PubMed1997

Th1-type immunity is incompatible with successful pregnancy.

Several years ago, the rather provocative question was raised: is successful pregnancy a T helper 2 (Th2) phenomenon? Implicit in this argument is the corollary that unsuccessful pregnancy is a Th1-type situation. Here, evidence from murine and human pregnancy is presented to show that, since Th1-type cytokines mediate pregnancy loss, a shift towards Th1-type immunity may help resolve 'unexplained' pregnancy failure.

Abortion, Spontaneous↗
PubMed1997

Maternal anti-placental cell-mediated reactivity and spontaneous abortions.

PROBLEM: Does Th1/Th2 balance determine pregnancy outcome, and if so, what determines Th1/Th2 balance in pregnancy? METHOD: Review and synthesis of existing data. RESULTS: A bias toward Th1 is strongly correlated with pregnancy failure in mice and humans. Pregnancy usually shifts the balance toward Th2 and placental factors/progesterone and progesterone-stimulated CD8+ T cell production of suppressor factor; TGFbeta2 and IL4/10 may be responsible. The bias toward a Th1 response may result from intracellular parasitic infection and other as yet undefined factors. CONCLUSION: The Th1/Th2 balance thesis appears to be valid.

Abortion, Habitual↗
PubMed1996

Hughes syndrome: a common problem in Kuwait hospitals.

The objective was to study antiphospholipid antibody syndrome (APS or Hughes syndrome) in two major teaching hospitals in Kuwait. patients with suspected Hughes syndrome were investigated with tests for anticardiolipin antibodies (aCL) and lupus anticoagulants (LAC) over 1 yr. Diagnosis was considered confirmed if significant levels of either or both antibodies with no obvious cause (primary), or with systemic lupus erythematosus (SLE) or SLE-like illness (including SLE serology) (secondary) were present. Twelve (37.5%; seven females, 58%) primary and 20 (62.5%; 18 females, 90%) secondary Hughes syndrome patients were seen during this period. patients were Kuwaiti, Middle-Eastern and North-African Arabs (29). Filipinos (2) and White (1). None were from the Indian subcontinent. The main presentation was thrombosis in 75% (arterial in 25% and venous in 50%), and recurrent abortions in 50% of married women. Haematological and dermatological manifestations were limited entirely to the secondary variety, seen in 25% and 19%, respectively. Clinical manifestations were severe, leading to death in one, intensive-care management in 31% and with partial or complete warfarin resistance or brittleness in 25%. Neurological/eye and cardiac manifestations were not seen, as these patients may be attending separate speciality hospitals for these diseases in Kuwait. The approximate prevalence of this syndrome was 2.66/1000 admissions in medical wards. Projected to the total referral areas of the two hospitals, an approximate figure of 52 patients/million population/year was obtained. Hughes syndrome was a common problem among Arabs, Filipinos and possibly Whites in Kuwait. Its manifestations were severe, often requiring intensive-care management, and in one case it was fatal. Patients from the Indian subcontinent were conspicuous by their absence, despite the fact that they were well represented in all other rheumatic disease groups. Ethnic and/or geographical factors could be important in this syndrome. To the best of our knowledge, this is the first report of Hughes syndrome from the Middle East.

Adolescent↗
PubMed1995

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.

CBA x DBA/2 placentae are quantitatively or qualitatively deficient in their production of the anti-inflammatory Th2-type cytokines IL-4 and IL-10 compared with the nonresorption-prone CBA x BALB/c mating combination. Wastage in this mating combination is accompanied by increased levels of local inflammatory cytokines. In addition, alloimmunization enhances the placental production of IL-4 and IL-10 in CBA x DBA/2 matings. Furthermore, rIL-10 by itself completely reverses the high incidence of fetal resorption after i.p. injection. Conversely, anti-IL-10 increases the resorption rate, but only in CBA x DBA/2 matings. On the other hand, injecting either anti-IFN-gamma or pentoxifillin (an anti-TNF agent) partially reduces the resorption. When given together, they produce a synergistic remission of fetal loss. Finally, we report that recombinant ovine trophoblast protein, an IFN-tau which is known to influence reproductive outcome in ruminants, can also counteract increased CBA x DBA/2 fetal resorption. It simultaneously induces increased placental IL-4 and IL-10 production in this mating combination. These results indicate that the placentally produced anti-inflammatory cytokines can play a vital role in the survival to term of the fetal allograft, by counteracting deleterious inflammatory cytokines.

Abortion, Spontaneous↗
PubMed1995

Carrier-induced epitope-specific regulation and its bypass in a protein-protein conjugate.

In the course of clinical trials on a birth control vaccine, it was found that some of the immunized women responded poorly to booster immunizations. This vaccine consists of a dimer of the beta chain of human chorionic gonadotropin (beta hCG) and the alpha chain of ovine luteinizing hormone (alpha oLH), linked to tetanus toxoid (TT) as a carrier. Changing this carrier to diphtheria toxoid resulted in reversion to high anti-hCG antibody titers, indicating the extent to which the carrier influences anti-ligand responses in this system. The suppression of anti-hCG responses after booster immunizations was reminiscent of the phenomenon of carrier-induced, epitope-specific regulation. In a mouse model designed to test the effects of preimmunization with TT on anti-hCG responses, we found that a single preimmunization with TT causes reduced anti-hCG antibody responses in two out of four mouse strains, while anti-alpha oLH antibody responses were not affected by the preimmunization with TT. This is particularly interesting considering that beta hCG and alpha oLH were not presented when linked separately to TT. In an effort to devise a strategy to circumvent this carrier-induced, ligand-specific hyporesponsiveness, we investigated the effectiveness of a synthetic T helper epitope from TT as carrier. We show that preimmunization with TT causes a less profound reduction in anti-hCG titers if the preimmunized mice are subsequently injected with alpha oLH-beta hCG conjugated to a synthetic tetanus toxin peptide recognized by TT-induced and peptide-induced T cells.

Amino Acid Sequence↗
PubMed1995

Characterization of an immunosuppressive factor secreted by a human trophoblast-derived choriocarcinoma cell line.

Factors and cells of placental origin have been considered to be important in mediating local active immunosuppression that regulates maternal immune reactivity to aid fetal survival. In this context, we investigated the immunosuppressive capabilities of supernatants from human trophoblast-derived choriocarcinoma cell lines (HCS). We have previously reported the inhibitory effects of HCS on proliferative responses of T-lymphocytes both in vitro and in vivo (L. Krishnan, E. Menu, G. Chaouat, G. P. Talwar, and R. Raghupathy, Cell. Immunol. 138, 113, 1991; L. Krishnan, R. Kinsky, G. Chaouat, G.P. Talwar, and R. Raghupathy, Cell. Immunol. 150, 376, 1993). We now show that HCS also suppresses LPS-induced proliferation of murine lymphocytes but does not inhibit the constitutive proliferation of lymphoma cell lines and B cell hybridomas indicating that HCS has no inhibitory effects on terminally differentiated or transformed cells. Furthermore, we have succeeded in isolating and partially characterizing the HCS-derived suppressor factor (HCSf) from culture supernatants of a human choriocarcinoma cell line JEG-3. Purification of the factor has been accomplished by sequential fractionation on anion-exchange, gel filtration, and reverse-phase HPLC columns. The suppressor factor is a low-molecular-weight compound in the range of 5-6 kDa, composed predominantly of hydrophilic amino acids. Protease digestion of the factor revealed that the peptide moiety in HCSf is important for its inhibitory activity. HCSf mediates a dose-dependent suppression of proliferative responses of both human and murine lymphocytes.

Amino Acids↗
PubMed1995

Immuno-endocrine interactions in early pregnancy.

First we recall briefly the status of inflammatory cytokines in the early implantation period. We then describe the status of leukaemia inhibiting factor (LIF) production in an in-vitro, relatively short-term, human decidual explant culture system. We show that in most infertile women with recurrent implantation failure following successful in-vitro fertilization, LIF production is statistically much lower than normal. Other parameters of LIF production in vitro are summarized briefly, and the effects of RU486 are shown. The TH2 status of normal pregnancy is described, together with the production of TH2 cytokines by decidua and placenta. These cytokines are deficient in the CBAXDBA/2 model of murine spontaneous early pregnancy loss. The defect can be corrected by alloimmunization, and more importantly by the injection of tau interferon. The significance of these data for early pregnancy signalling is discussed.

Animals↗
PubMed1994

Maternal anti-placental reactivity in natural, immunologically-mediated fetal resorptions.

Observations on maternal recognition of the fetus and the demonstration of the effects of cytokines on reproductive events led to the "immunotrophism" model, which suggests that maternal immune recognition of fetally-derived Ags results in the release of cytokines that promote the growth of the placenta; any disturbance in this balance of cytokines could result in deleterious consequences for the placenta and, in turn, the fetus. We have focused our attention on the murine CBA/J x DBA/2 model of spontaneous abortions and compared them with normal CBA x BALB/c pregnancies. Our results indicate that the extent of stimulation of maternal strain lymphocytes in response to stimulator placental cells in mixed lymphocyte-placenta reactions (MLPR) was much higher in the normal mating combination compared with the abortion-prone mating combination. Cytokine analysis of the supernatants from MLPR indicates that there is significantly higher production of TNF-alpha, IFN-gamma, and IL-2 in supernatants from the abortion-prone combination than in supernatants from the normal combination. Furthermore, MLPR-stimulated cells induce resorptions in normal pregnant mice; maternal strain lymphocytes stimulated by placentas from the abortion-prone combination induce high rates of fetal resorptions, but lymphocytes stimulated with placentas from the normal combination do not. Together, these results suggest that immunologically mediated fetal resorptions probably result from improper or inappropriate maternal responses to placental Ags. Our observations also suggest that such effects are probably mediated by cytokines.

Animals↗
PubMed1993

Suppression of local and systemic GVHR by supernatants from human choriocarcinoma cell lines.

Graft versus host reaction (GVHR) and host versus graft reactivity during pregnancy share at least some cellular pathways. Immunosuppression mediated by placental suppressor factors may actively contribute to the survival of the conceptus in the immunocompetent mother. We have previously reported that supernatants from human choriocarcinoma cell lines inhibit mitogen-activated and antigen-activated proliferation of lymphoid cells. From this perspective, we investigated the capacity of supernatants from human choriocarcinoma cell lines (HCS) to suppress in vivo graft versus host reactions in mice. HCS was tested for its ability to block both local as well as systemic GVHR induced by the injection of parental cells into F1 mice. HCS mediates profound suppression of acute and chronic GVHR. These results confirm that human choriocarcinoma cell lines secrete a potent immunosuppressive factor(s) which can efficiently modulate immune responses in vivo.

Animals↗
PubMed1993

Synthetic gonadotrophin-releasing hormone (GnRH) vaccines incorporating GnRH and synthetic T-helper epitopes.

A vaccine against the gonadotrophin-releasing hormone (GnRH) is being developed as an immunological method for treatment of prostatic hypertrophy, based on the observation that active immunization against GnRH leads to the production of anti-GnRH antibodies which results in the shrinkage of the prostate gland. We have been investigating the regulation of anti-GnRH antibody responses by carrier molecules. In previous studies we showed that the use of large protein molecules as carriers limits the use of such a vaccine owing to potential problems of carrier-induced anti-haptenic suppression. In this report we show that synthetic T-helper epitopes can be used as carriers for the generation of anti-GnRH antibody responses.

Animals↗
PubMed1993

Expression of cytokines in placentas of mice undergoing immunologically mediated spontaneous fetal resorptions.

It is clear that the immune system and the reproductive system interact with and influence each other and that the immune system can have positive and negative regulatory effects on the outcome of pregnancy. The discovery of murine models of immunologically mediated spontaneous fetal resorptions has proved to be very useful for the study of immunological influences on pregnancy. In an attempt to elucidate the mechanisms underlying pregnancy impairment in one such "natural" model of pregnancy loss, we compared the expression of the cytokines tumor necrosis factor alpha, interferon tau, and interleukin-2 in placental tissue from a resorption-prone strain combination with the expression from a normal combination. We found significantly enhanced expression of these three cytokines in placentas from the resorption-prone combination using dot-blot hybridization and Northern hybridizations. Since these cytokines are abortifacients in vivo and have detrimental effects on the placenta, and hence on fetal development and survival, our demonstration of enhanced expression of these deleterious cytokines may give insight into the mechanisms involved in immunologically mediated spontaneous abortions.

Animals↗
PubMed1992

Binding of sperm to somatic cells via HLA-DR. Modulation by sulfated carbohydrates.

We have shown previously that human sperm bind and enter leukocytes expressing surface HLA class II molecules. In the present study, mutant B lymphoblastoid cells and HLA-DR-transfected murine 3T3 fibroblasts are used to confirm that HLA class II molecules are somatic cell receptors for sperm. Further, for isolated HLA-DR expressed on murine cells, we show that sperm receptor activity requires the presence of sulfated carbohydrates. As carriers of multiple HLA-DR binding ligands, sperm may 1) mimic the target cell-activating effects of anti-DR antibody and 2) bind HIV through CD4-like or alternate receptors. By these or other mechanisms, sperm/somatic cell interactions in the female reproductive tract may affect fertility and potentiate the sexual transmission of AIDS.

3T3 Cells↗
PubMed1992

Vaccines against fertility.

The first evidence for the efficacy of a birth control vaccine in humans is now available from the Phase II trials on the human chorionic gonadotrophin vaccine in India. Several sperm antigens have been identified as potential contraceptive immunogens and zona pellucida antigens have been reported that reversibly control fertility.

Chorionic Gonadotropin↗
PubMed1992

A single human monoclonal antibody that confers total protection from tetanus.

Protective human monoclonal antibodies (HuMAbs) are superior to hyperimmune sera and murine monoclonal antibodies as far as human immunotherapy is concerned. In this report, we describe the successful generation of triomas secreting HuMAbs to tetanus toxin (tt). Lymphoblastoid cell lines secreting anti-tt antibodies were stabilized by back-fusion with a mouse x human heterohybrid myeloma partner, SBC-H20. One of the antibodies so produced, confers total protection of mice from tetanus, unlike a few recent reports where only partial protection (delay in the onset of tetanus) was achieved with single HuMAbs. Experiments to localize the neutralizing epitope(s) of the toxin using the protective monoclonal antibodies revealed that the antibody recognizes a conformational determinant that is destroyed on SDS-treatment. Preliminary studies show that Fab preparations of the protective antibody are capable of neutralizing tetanus toxin, suggesting that it might be possible to clone and express the Fab in a stable vector for large scale production.

Animals↗
PubMed1992

Bypass of carrier-induced epitope-specific suppression using a T-helper epitope.

A gonadotropin-releasing hormone (GnRH)-based vaccine is being developed as a method for non-surgical immunotherapy as immunization with this vaccine results in atrophy of the prostate. This vaccine, a conjugate of GnRH and diphtheria toxoid (DT), provides a unique hapten-carrier system for investigating the influence of carrier presensitization on antibody responses to self haptens. In a recent communication we showed that preimmunization with carriers diphtheria toxoid and tetanus toxoid results in a strain-dependent inhibition of anti-GnRH responses in mice and that T cells from carrier-presensitized mice are responsible for anti-haptenic suppression. In the present report we describe a strategy for bypassing DT-induced epitopic suppression using a T-helper epitope from DT.

Animals↗
PubMed1991

In vitro and in vivo immunosuppressive effects of supernatants from human choriocarcinoma cell lines.

Local immunosuppression mediated by placental suppressor factors may contribute to the absence of consistently demonstrable cellular immunity against the fetus. In this context, we have investigated the immunosuppressive capabilities of supernatants from human trophoblastic choriocarcinoma cell lines (HCS) by testing the effects of HCS on immune responses in vitro and in vivo in the human and murine systems. HCS suppresses mitogen-induced proliferation and mixed lymphocyte reactions in humans and in mice, as well as antigen-induced T cell proliferation in mice. HCS also suppresses the in vivo response of mice to allogeneic cells. Furthermore, HCS when injected intraperitoneally causes the induction of suppressor cells in mice which in turn prevent the mounting of an allogeneic response in other strains of mice. These results indicate that human choriocarcinoma cell lines secrete a suppressor factor(s) which induces suppression in vitro as well as in vivo through the generation of suppressor cells.

Choriocarcinoma↗