V. K. Singh

THE PARADIGM OF TH1 AND TH2 CYTOKINES : ITS RELEVANCE TO AUTOIMMUNITY AND ALLERGY

In the past few years, considerable evidence has accumulated to suggest the existence of functionally polarized responses by the CD4+ T helper (Th)—and the CD8+ T cytotoxic (Tc)—cell subsets that depend on the cytokines they produce. The Th1 and Th2 cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The factors responsible for the polarization of specific immune response into a predominant Th1 or Th2 profile have been extensively investigated in mice and humans. Evidence has accumulated from animal models to suggest that Th1type lymphokines are involved in the genesis of organ-specific autoimmune diseases, such as experimental autoimmune uveitis, experimental allergic encephalomyelitis, or insulin-dependent diabetes mellitus. Accordingly, data so far available in human diseases favor a prevalent Th1 lymphokine profile in target organs of patients with organ-specific autoimmunity. By contrast, Th2-cell predominance was found in the skin of patients with chronic graft-versus host disease, progressive systemic sclerosis, systemic lupus erythematosus, and allergic diseases. The Th1/Th2 concept suggests that modulation of relative contribution of Th1 or Th2-type cytokines regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologie disorders. In this review, we have discussed the paradigm of Th1 and Th2 cytokines in relation to autoimmunity and allergy.

Immunomodulatory Effects of Curcumin

Curcumin (diferuloylmethane), found in the spice turmeric, exhibits anti-inflammatory, antioxidant, and chemopreventive activities. However, the effect of curcumin on the immunological responses largely remains unknown. In this study we have investigated the effect of curcumin on mitogen (phytohaemagglutinin; PHA) stimulated T-cell proliferation, natural killer (NK) cell cytotoxicity, production of cytokines by human peripheral blood mononuclear cells (PBMCs), nitric oxide (NO) production in mouse macrophage cells, RAW-264.7. Furthermore, we have carried out an electromobility shift assay to elucidate the mechanism of action of curcumin at DNA protein interaction level. We observed that curcumin inhibits PHA-induced T-cell proliferation, interleukin-2 production, NO generation, and lipopolysachharide-induced nuclear factor-κB (NF-κB) and augments NK cell cytotoxicity. Our results suggest that curcumin most likely inhibits cell proliferation and cytokine production by inhibiting NF-κB target genes involved in the induction of these immune parameters.

Anticellular and immunosuppressive properties of ethanolic extract of Acorus calamus rhizome

Modulation of immune response to alleviate disease has been of interest since long. Plant extracts have been widely investigated for possible immunomodulatory properties. We have evaluated the anticellular and immunomodulatory properties of ethanolic extract of Acorus calamus rhizome. This extract inhibited proliferation of mitogen (phytohaemagglutinin; PHA) and antigen (purified protein derivative; PPD)-stimulated human peripheral blood mononuclear cells (PBMCs). In addition, A. calamus extract inhibited growth of several cell lines of mouse and human origin. It also inhibited production of nitric oxide (NO), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha). Intracytoplasmic interferon-gamma (IFN-gamma) and expression of cell surface markers, CD16 and HLA-DR, on human PBMC, were not affected on treatment with A. calamus extract but CD25 expression was down regulated. Our study demonstrates the antiproliferative and immunosuppressive potential of ethanolic extract of A. calamus rhizome in vitro.

Modulation of autoimmune diseases by nitric oxide.

Nitric oxide (NO) is an intercellular messenger that performs a number of functions, including neurotransmission, vasodilatation, inhibition of platelet aggregation, and modulation of leukocyte adhesion. NO has recently been shown to act as a potent cytotoxic effector molecule as well as to play an important role in the pathogenesis of organ-specific autoimmunity. NO may also modulate the immune response by interfering with Th1/Th2 balance in autoimmune diseases. This review will discuss the role of NO and nitric oxide synthase (NOS) in pathophysiologic and therapeutic implications in various autoimmune diseases with particular reference to T helper-1 (Th1) and T helper-2 (Th2) cytokines.

Effect of lead exposure on the immune response of some occupationally exposed individuals

Lead is a ubiquitous pollutant in the industrial environment, which poses serious threats to human health. In the past 20 years increasing attention has been paid to the effects of lead exposure on health. This toxic metal alters the immune response of animals as well as humans. To study the immunological effects of occupational exposure to lead, we examined lymphocyte proliferation, natural killer (NK) cell cytotoxicity and interferon-gamma production with peripheral blood mononuclear cells (PBMCs) of individuals occupationally exposed to lead. We selected three different groups of individuals exposed to lead: three-wheeler drivers (30), battery workers (34) and silver jewelery makers (20); and unexposed healthy volunteers (30) as control for comparison. Our results indicate that though lymphocyte proliferation to phytohaemagglutinin (PHA) is inhibited in lead exposed individuals as compared with unexposed volunteers, there is no correlation between inhibition of lymphocyte proliferation and blood lead level. NK cell cytotoxicity remains unaffected in individuals exposed to lead as compared with controls. On the other hand, we observed that interferon-gamma (IFN-gamma) was significantly elevated in T cell mitogen, PHA, stimulated PBMCs culture supernatant of lead exposed individuals. We found significant positive correlation between blood lead levels and IFN-gamma produced in culture supernatant on stimulation with PHA. In brief, this study demonstrates that lead can affect the immune response of the occupationally exposed individuals such as three-wheeler drivers, battery reconditioning workers and silver jewelery makers.

Immunomodulation by ethanolic extract of Boerhaavia diffusa roots

We have earlier reported that ethanolic extract of Boerhaavia diffusa, a plant used in Indian traditional system of medicine, significantly inhibits the cell proliferation. This led us to evaluate the immunomodulatory properties of this plant extract on various in vitro tests such as human natural killer (NK) cell cytotoxicity, production of nitric oxide (NO) in mouse macrophage cells, RAW 264.7, interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), intracytoplasmic interferon-gamma (IFN-gamma) and expression of various cell surface markers on human peripheral blood mononuclear cells (PBMCs). Ethanolic extracts of B. diffusa roots inhibited human NK cell cytotoxicity in vitro, production of NO in mouse macrophage cells, IL-2 and TNF-alpha in human PBMCs. Intracytoplasmic IFN-gamma and cell surface markers such as CD16, CD25, and HLA-DR did not get affected on treatment with B. diffusa extract. Our study demonstrates immunosuppressive potential of ethanolic extract of B. diffusa.

Thymopentin and splenopentin as immunomodulators. Current status.

Splenopentin (SP-5, Arg-Lys-Glu-Val-Tyr) and thymopentin (TP-5, Arg-Lys-Asp-Val-Tyr) are synthetic immunomodulating peptides corresponding to the region 32–34 of a splenic product called splenin (SP) and the thymic hormone thymopoietin (TP), respectively. TP was originally isolated as a 5-kDa (49-amino acids) protein from bovine thymus while studying effects of the thymic extracts on neuromuscular transmission and was subsequently observed to affect T cell differentiation and function. TP I and II are two closely related polypeptides isolated from bovine thymus. A radioimmunoassay for TP revealed a crossreaction with a product found in spleen and lymph node. This product, named splenin, differs from TP only in position 34, aspartic acid for bovine TP and glutamic acid for bovine splenin and it was called TP III as well. Synthetic pentapeptides (TP-5) and (SP-5), reproduce the biological activities of TP and SP, respectively. It is now evident that various forms of TPs were created by proteolytic cleavage of larger proteins during isolation. cDNA clones have been isolated for three alternatively spliced mRNAs that encodes three distinct human T cell TPs. The immunomodulatory properties of TP, SP, TP-5, SP-5 and some of their synthetic analogs reported in the literature have been briefly reviewed.

Molecular Biology of Opioid Receptors: Recent Advances

Endogenous opioid peptides and opiates like morphine produce their pharmacological effects through the membrane bound opioid receptors. These receptors belong to a superfamily of G-protein-coupled receptors, all of which possess seven membrane-spanning regions. Structure-activity relationship studies of opioids opened up new avenues for the pharmacological characterization of the opioid receptors. As a further advancement in this direction, molecular cloning has led to the identification of three different types of opioid receptors -- OP1 (delta), OP2 (kappa) and OP3 (mu) -- thereby supporting the results of earlier pharmacological studies which postulated their existence. The three opioid receptors are highly homologous. Consequent to the development of highly specific and selective agonists and antagonists, it was proposed that the three types of opioid receptors could be further categorized into different subtypes. However, the molecular biology data generated so far do not support the presence of the various subtypes of the three well-characterized opioid receptors. Recent strides towards the advancement of our knowledge relating to the molecular biology of these receptors have been reviewed in this article.

Immunomodulation by lead

Lead, a potential human carcinogen, is a ubiquitous environmental pollutant in the industrial environment that poses a serious threat to human health. This toxic lead can modulate the immune response of animals as well as humans. In some instances, the immune system appears to be exquisitely sensitive to lead as compared with other toxicological parameters. Both stimulation and suppression of immune response have been demonstrated in lead exposed animals and humans depending on the T helper (Th)1 vs Th2 response. Although the majority of data accumulated to date pertains to the effects of lead in small laboratory rodents, there is little reason to believe that similar quantifiable effects do not occur in domestic and food-producing animals owing to basic functional similarities of the immune system of mammals. In this review, we have discussed the immunomodulatory role of the toxic heavy metal, lead, on cellular and humoral components of the immune system with particular reference to effector cells such as B cells, T cells, natural killer (NK) cells, and soluble mediators such as cytokines, chemokines, and nitric oxide (NO).

CELLULAR IMMUNE RESPONSE TO RETINAL S-ANTIGEN AND INTERPHOTORECEPTOR RETINOID-BINDING PROTEIN FRAGMENTS IN EALES' DISEASE PATIENTS

The role of retinal antigens in Eales’ disease was studied in 24 patients and an equal number of healthy controls. Lymphocyte proliferative responses were tested in vitro against native S-antigen, its uveitopathogenic peptides (peptide M and peptide G), yeast histone H3 peptide and uveitopathogenic fragment of interphotoreceptor retinoid-binding protein (IRBP; R16) to establish their role in the pathogenesis of Eales’ disease. Out of 24 Eales’ disease patients, 6 showed significant proliferative response against S-antigen, its uveitogenic fragments or IRBP. None among the controls showed any response to any retinal antigen used in this study. There was no statistically significant difference in the response to purified protein derivative between patients and controls. These results suggest that retinal antigens may play a role in the etiopathogenesis of Eales’ disease. An extraneous agent that could result in exposure of normally sequestered uveitopathogenic antigens of the immune system, leading to an exuberant immune response in the eye may initiate the disease.