Immunoregulatory Drugs Research Articles

Immune regulation by regulatory T cells: implications for transplantation

The induction of antigen-specific T cell tolerance and its maintenance in the periphery are critical for the immune system to prevent autoaggressive immune responses. Our current state of knowledge about the immunoregulatory mechanisms responsible for T cell tolerance in the periphery offers new possibilities for immunomodulation to prevent transplant rejection as well as to diminish autoimmune reaction or chronic allergy. There is growing evidence that dendritic cells, besides their well-known T cell stimulatory functions, also maintain and regulate T cell tolerance in the periphery. This control function is exerted by certain maturation stages and subsets of dendritic cells, and can be further influenced and modulated by immunoregulatory cytokines and drugs. The regulatory functions of dendritic cells include the induction of T cell anergy, of T cells with regulatory properties and of T cells that produce immunosuppressive cytokines such as IL-10 or TGF-β. Additionally, distinct subsets of resident regulatory T cells generated in the thymus play a central role in maintenance of peripheral tolerance by active suppression of effector T cell populations. These CD4 +CD25 + regulatory T cells inhibit a variety of autoimmune and inflammatory diseases and they are also efficient in the suppression of alloantigen responses. This review summarises the current knowledge regarding the immunoregulatory role of dendritic cells and the functional activities of resident regulatory T cells as guardians for peripheral T cell tolerance.

Total Enantioselective Synthesis and in vivo Biological Evaluation of a Novel Fluorescent BODIPY α‐Galactosylceramide.

ChemInformVolume 34, Issue 14 Natural Products Total Enantioselective Synthesis and in vivo Biological Evaluation of a Novel Fluorescent BODIPY α-Galactosylceramide. Yen Vo-Hoang, Yen Vo-Hoang Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorLaurent Micouin, Laurent Micouin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorCatherine Ronet, Catherine Ronet Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorGabriel Gachelin, Gabriel Gachelin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorMartine Bonin, Martine Bonin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this author Yen Vo-Hoang, Yen Vo-Hoang Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorLaurent Micouin, Laurent Micouin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorCatherine Ronet, Catherine Ronet Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorGabriel Gachelin, Gabriel Gachelin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorMartine Bonin, Martine Bonin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this author First published: 20 March 2003 https://doi.org/10.1002/chin.200314228Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume34, Issue14April 8, 2003 RelatedInformation

Total enantioselective synthesis and in vivo biological evaluation of a novel fluorescent BODIPY alpha-galactosylceramide.

Natural killer T (NKT) cells are a distinct subset of mature lymphocytes endowed with features of activated and regulatory T cells. alpha-Galactosylceramides (alpha-GalCers), the synthetic prototype of which is KRN7000, are the only natural reagents recognised by the T-cell receptor of NKT cells. The alpha-GalCer-activated NKT cells promptly release IFN gamma and IL-4 (IFN=interferon; IL=interleukin) and undergo apoptotic death within hours. In mice, activated NKT cells are responsible for antitumour activity and protection against autoimmune diseases. KRN7000 can thus be considered as the root of a family of novel immunoregulatory drugs. To get insights into the in vivo behaviour of alpha-galactosylceramides, an original fluorescent derivative has been prepared by following a convergent synthetic scheme. This strategy allows the introduction of different acyl chains, carbohydrate residues and various labels in the final steps of the synthesis. The fluorescent BODIPY probe derived from a versatile glycolipid precursor is as active as KRN7000 for inducing apoptosis of liver NKT cells. Fluorescence was detected in peritoneal macrophages and splenic antigen-presenting cells, in Kupffer-like cells in the liver, but not in lymphocytes.

Effects of immunoregulatory drugs on human peripheral blood T lymphocytes function in vitro

BACKGROUND: The purpose of the study was to evaluate the mode of action of different immunoregulatory drugs in lymphocyte proliferation and activation METHODS: The drugs studied were prednisolone (PRED), cyclosporin A (CsA) the recombination of PRED and CsA, L-asparaginase and cytosine-arabinose (ara-C). Peripheral blood lymphocytes from normal blood donors were stimulated by phytohemagglutinin (PHA). Lymphocytes proliferation and activation were determined by tritiated thymidine ([3H]TdR) incorporation secretion of interleukin-2, level of soluble interleukin-2 receptors in the supernatant of the culture medium, and immunophenotyping analysis of T lymphocyte subsets. RESULTS: Among PRED CsA and their combination, the strongest inhibition of cell proliferation was induced by PRED while L-asparaginase and ara-C inhibited PHA stimulated T cells proliferation in concentration and time dependent manner. Among PRED, CsA and their combination, CsA induced the greatest inhibition of IL-2 production. All the immunoregulatory drugs inhibited lymphocyte proliferation and expression of activation antigens. CONCLUSION: The immunoregulatory drugs inhibit both lymphocyte proliferation and activation but in a different way.

Natural T cell immunity to intracellular pathogens and nonpeptidic immunoregulatory drugs.

Natural T (NT) lymphocytes recognize infected cells or microbial compounds without the classical genetic restriction of polymorphic major histocompatibility complex (MHC) molecules. This innate recognition pathway results in a broad and rapid antimicrobial response that may be critical for controlling the spread of intracellular pathogens, requiring the elimination of the infecting agent from both extracellular spaces and host cells. NT cells are mainly composed of alphabeta and gammadelta T lymphocytes that express natural killer (NK) receptors and recognize preferentially various nonpeptidic antigens. Similar to NK cells, NT lymphocytes can 'see' and kill target cells deficient in the expression of one or more MHC class I molecules. NT cells expressing the alphabeta TCR can recognize lipid and lipoglycan antigens presented in the context of nonpolymorphic CD1 molecules, whereas phosphocarbohydrates and akilamines induce constitutive responses in most Vgamma9Vdelta2 NT lymphocytes. The remaining fraction of gammadelta NT cells express the Vdelta1 chain associated with different Vgamma-chains and may directly recognize self-antigens such as MICA, MICB or CD1 molecules. It is possible that NT lymphocytes may play two opposite roles during intracellular infections. First, in the acute phase, they may be critical for the initiation of pathogen elimination. Second, in the chronic phase, NT cells may be dangerous, if their potential autoreactivity is not well controlled. It is conceivable that novel strategies of immune intervention against emerging and re-emerging intracellular pathogens, such as human immundeficiency virus (HIV), hepatitis-C virus (HCV) and Mycobacterium tuberculosis (MTB) may involve the control of NT cell activation/anergy by (nonpeptidic) immunoregulatory drugs.

Immunoregulatory drugs: mechanistic basis for use in organ transplantation.

Multiple immunoregulatory drugs, capable of constraining cell activation, differentiation, and/or proliferation, and each with distinct side effects, are currently used in the clinic to facilitate organ engraftment. Cyclosporine, azathioprine, corticosteroids, FK506 (tacrolimus), and RS61443 (mycophenolate mofetil) have already been approved by the United States Food and Drug Administration. Rapamycin (sirolimus), mizoribine, and 15-deoxyspergualin are being explored for their clinical efficacy. Based on their subcellular site of action, the immunosuppressants can be considered as: inhibitors of transcription (cyclosporine, tacrolimus), inhibitors of nucleotide synthesis (azathioprine, mycophenolate mofetil, mizoribine), inhibitors of growth factor signal transduction (sirolimus), and inhibitors of differentiation (15-deoxyspergualin). Clearly, the transplant clinician now has a greater choice in the selection and application of immunosuppressants in the clinic for the fine regulation of anti-allograft immunity. The existing hypothesis regarding the mechanisms of action of immunosuppressants is that they all function to prevent allograft rejection by preventing/inhibiting cell activation, cytokine production, differentiation, and/or proliferation. A complementary supposition is that some of the immunosuppressants might regulate the anti-allograft repertory by stimulating the expression of immunosuppressive molecules and/or cells.

A comparison of several agents with two delivery systems for the prevention of airway narrowing induced by nebulised pentamidine isethionate

Bronchial narrowing is the major side effect of inhaled nebulised pentamidine isethionate, used for the prophylaxis and treatment of Pneumocystis carinii pneumonia. Several agents and delivery systems were assessed for prophylaxis of bronchial narrowing in HIV-positive males receiving regular nebulised pentamidine isethionate. In a previous study we found the mean maximum fall in FEV1 with nebulised pentamidine alone to be 21%. FEV1 was measured before and after inhaling nebulised pentamidine, preceded by one of the following bronchodilator/immunoregulatory agents: Terbutaline metered dose inhaler (500 micrograms), nebulised salbutamol (5 mg), nebulised ipratropium bromide (500 micrograms), nebulised sodium cromoglycate (20 mg), and nedocromil sodium metered dose inhaler (4 mg). Each agent was administered once only to ten different subjects. Nebulised salbutamol gave most effective prophylaxis against bronchial narrowing induced by nebulised pentamidine (mean maximum fall in FEV1 = 5% vs. 21%, P less than 0.001). Terbutaline given by metered dose inhaler was significantly less effective than high dose terbutaline (10 mg) given by nebuliser, demonstrated in the previous study (mean maximum fall in FEV1 = 14% vs. 6%, P less than 0.05). Mean maximum falls in FEV1 for ipratropium bromide, sodium cromoglycate and nedocromil sodium were 16, 17 and 16%, respectively. High dose beta 2-agonists administered by nebuliser give more effective prophylaxis against nebulised pentamidine-induced bronchial narrowing than either lower doses given by metered dose inhaler, anticholinergics or immunoregulatory drugs.

Murine delayed-type hypersensitivity granuloma: An improved model for the identification and evaluation of different classes of anti-arthritic drugs

The present study examined the effects of five different classes of anti-inflammatory/ immunoregulatory drugs using a mouse model of mBSA-induced delayed-type hypersensitivity granuloma (DTH GRA) to measure immune-mediated chronic inflammatory tissue formation. The compounds were administered orally daily following induction of DTH GRA (days 0 to 4); granulomata were quantitated gravimetrically on day 5. NSAIDs, with the exception of flurbiprofen, showed little activity in comparison with the steroids dexamethasone (1—3 mg/kg/day, orally) and prednisolone (3–10 mg/kg/day, orally), which caused significant suppression of DTH GRA tissue (65–76% and 26–68%, respectively). The “immunoregulatory” compounds levamisole and D(−)penicillamine were inactive, whereas cyclophosphamide (5–50 mg/kg/day, orally) reduced the response by 24–83%. The “interferon α-inducers” Tilorone, U-54, 461, and U-56,499 were also potent inhibitors of the DTH GRA response; U-54,462, a weak interferon α-inducer, was inactive. Cyclosporin A (50–100 mg/kg/day, orally) suppressed DTH GRA most effectively when administered on days 3 and 4 (66% and 97%) of the five-day granuloma response (treatment was ineffective when given on days 1 and 2). We conclude that the DTH GRA response described above may be useful for evaluating different types of unique therapeutic agents that are effective in the treatment of chronic immuno-inflammatory diseases such as rheumatoid arthritis.

Alteration of infection pattern of duck hepatitis B virus by immunomodulatory drugs.

The relationship between host immune state and hepatic inflammation and infection pattern of the Duck hepatitis B virus (DHBV) was investigated by experimental transmission of DHBV into 98 Japanese 7-day-old ducklings that had been pretreated with immunoregulatory drugs including cyclophosphamide, OK 432, and a steroid hormone. Immunosuppressive treatment with cyclophosphamide revealed an extension of the viremic period associated with an absence of inflammatory changes in the liver. Although immunostimulating treatment with OK 432 showed a remarkable accumulation of inflammatory cells in the liver, the viremic period was not shortened. Treatment with a steroid used as a immunosuppressant did not suppress the hepatitis; moreover, it increased viral DNA replication and extended the viremic period. This phenomenon of viral replication seemed to be caused by the direct effects of the steroid. Alteration of DHBV infection by modifying the host immune state is quite similar to that of hepatitis B virus (HBV) in humans. In DHBV infection, the host immune state seemed to have a considerable role in determining the infection pattern and degree of hepatitis activity. DHBV may be a helpful model of HBV for studying host-viral interaction and the immunological mechanism of viral hepatitis.

Alteration of interleukin-1 production and the acute phase response following medication of adjuvant arthritic rats with cyclosporin-A or methotrexate

The purpose of the paper was to determine whether two clinically active antirheumatic compounds, cyclosporin-A (CS-A) and methotrexate (MTX) were efficacious in the treatment of adjuvant arthritis (AA) in rats, as measured by reduction of paw inflammation, lymphocyte activating factor (LAF) activity and the acute phase response. Parameters of the acute phase response consisted of plasma fibronectin (Fn), C-reactive protein (CRP), albumin and iron. Rats injected with Freund's complete adjuvant on day 1, developed systemic arthritis, which was quantitated by measuring non-injected paw swelling on day 17. When compared to normal animals, AA rats had significantly ( P⩽0.01) increased: (1) splenic LAF activity (100% increase), (2) plasma Fn (58%), and (3) CRP (122%), as well as abnormally reduced levels of: (1) plasma albumin (53% reduction), and (2) iron (54%). Orally dosing AA rats from days 3 to 17 with the immunoregulatory drugs, CS-A (3 and 5 mg/kg) or MTX (0.5 and 1 mg/kg), significantly ( P⩽0.01) reduced paw inflammation (100% reduction), increased final body wt 40 – 50 g over arthritic controls and decreased LAF activity from splenic leukocytes. The acute phase response, often associated with a high degree of LAF activity, was significantly ( P⩽0.01) decreased by dosing with CS-A (3 and 5 mg/kg) and MTX (0.5 and 1 mg/kg). The inhibition of the acute phase response was measured by reduction of high plasma Fn levels (42 – 79% decrease) and CRP levels (57 – 100% decrease) as well as elevation of subnormal levels of plasma albumin (57 – 101% increase) and iron (40 – 114% increase). Dosing with the nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin (50 and 100 mg/kg) or phenylbutazone (10 and 30 mg/kg), significantly inhibited paw inflammation (29 – 85%), but did not decrease the high rate of splenic LAF activity, nor did aspirin (55, 100 and 200 mg/kg) or phenylbutazone (1, 10 and 30 mg/kg) alter the acute phase response in AA rats, as measured by levels of plasma Fn, CRP, albumin and iron. Since CS-A and MTX have been reported to be effective in the treatment of RA, their activity in the LAF, Fn, CRP, albumin and iron assays of the AA rat suggests that these immunological and serological parameters may be useful in identifying potential antirheumatic drugs and distinguishing them from standard NSAIDs.