Trivendra Tripathi

Histamine, Histamine Receptors, and their Role in Immunomodulation: An Updated Systematic Review

Histamine, a biological amine, is considered as a principle mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. It stimulates different biological activities through differen- tial expression of four types of histamine receptors (H1R, H2R, H3R and H4R) on secretion by effector cells (mast cells and basophils) through various immunological or non-immunological stimuli. Since H4R has been discovered very re- cently and there is paucity of comprehensive literature covering new histamine receptors, their antagonists/agonists, and role in immune regulation and immunomodulation, we tried to update the current aspects and fill the gap in existing litera- ture. This review will highlight the biological and pharmacological characterization of histamine, histamine receptors, their antagonists/agonists, and implications in immune regulation and immunomodulation.

Dose-dependent effect of histamine on antibody generation in vivo

Objective: To delineate immunomodulatory role of histamine on antibody generation profile in rabbit in the present dose-dependent histamine study. Methods: The cohort comprised of three groups (Ⅲ. Ⅳ and Ⅴ), containing six rabbits each, and received subcutaneous histamine 50μg/kg×b. i. s in die (b. i. d.), 100μg/kg×b. i. d. and 200μg/kg×b. i. d., respectively for 10 days (starting from the 1st day). They were subsequently immunized on the 3rd day with intravenous injection of sheep blood cell (SRBC) (1×10^9 cells/mL). Group Ⅱ (positive control) (n=6) received vehicle (sterile distilled water) and immunized at day 3 similarly while group Ⅰ (negative control) (n=6) remained non-immunized and received only vehicle. All experimentations were performed in triplicate. Blood samples were collected on pre-immunization (pre-Ⅰ) (day 0). as well as on days 7-, 14-, 21-. 28- and 58-post-immunization (post-Ⅰ). Immunological parameters [total immunoglobulins (Igs). IgM and IgG] were analyzed by enzyme linked immunosorbent assay (ELISA) technique. Results: Histamine could influence a detectable antibody response to SRBC as early as day 7-post-Ⅰ. which lasted until day 58-post-Ⅰ. The results were found statistically significant (P＜0.05). Conclusions: Our results provide evidence that histamine has a short-term effect on antibody generation (until its presence in the body), and the antibody generation titer in vivo were affected by the concentration of histamine.

Modulation of in vivo immunoglobulin production by endogenous histamine and H1R and H2R agonists and antagonists

The present study was designed to delineate the immunomodulatory role of histamine receptors (H1R and H2R) and their antibody generation in a rabbit model. Six groups containing 18 rabbits each received either vehicle (sterile distilled water, 1 ml/kg x b.i.d), histamine (100 μg/kg x b.i.d.), H1R agonist (HTMT, 10 μg/kg x b.i.d.), H2R agonist (amthamine, 10 μg/kg x b.i.d.), H1R antagonist (pheniramine, 10 mg/kg x b.i.d.) or H2R antagonist (ranitidine, 10 mg/kg x b.i.d.). All animals were subsequently immunized with an intravenous injection of sheep red blood cells (SRBC). Estimations of total serum immunoglobulins (Igs), immunoglobulin M (IgM) and immunoglobulin G (IgG) were performed by ELISA and hemagglutination assay (HA) at days 0 (pre-immunization), 7, 14, 21, 28 and 58 (post-immunization). Both the ELISA and the HA showed similar production of Igs, IgM and IgG but the results were found comparatively more significant by ELISA as opposed to HA. Results showed that histamine could influence a detectable antibody response to SRBC early (i.e., at day 7), which lasted until day 58. Immunomodulatory processes showed suppression of an Ig generation in the H1R-antagonist group with enhancement in the H2R-antagonist group. The H1R-agonist group showed an increased Ig production in comparison to the H2R-agonist group. The IgM production was inhibited in the H1R-antagonist group as compared to the H2R-antagonist group, and it was also suppressed in H1R-agonist group as compared to H2R-agonist group. IgG production was inhibited in the H1R-antagonist group as opposed to the H2R-antagonist group. In contrast, the H1R-agonist group increased IgG production as compared to the H2R-agonist group. All the results were found to be statistically significant (p < 0.05 or p < 0.01). In conclusion, histamine and its receptor (H1R and H2R) agonists enhance antibody production by triggering the histamine receptors (H1R and H2R), and both the H1R antagonist and the H2R antagonist positively or negatively regulate the antibody production. The findings of this study may have clinical significance.

Immunological, biochemical and histopathological evaluation of histamine receptors (H1R, H2R, H3R and H4R)-antagonist in rabbit experimental model: A short term study

The present study was designed to delineate the immuno- and hepatotoxicological roles of HRs-antagonists in vivo which is elementary in existing literature. The cohort comprised of two experimental studies. Experimental study 1 was designed for immunological investigations and consisted of seven groups and immunized with intravenous injection of SRBC at day 3 containing six rabbits each. Experimental study 2 was designed to assess the functional status of liver and comprised of seven groups containing five rabbits each. In both experimental studies group-I received sterile distilled water intramuscularly, and group II-VI received subcutaneous histamine, pheniramine (H1R-antagonist), ranitidine (H2R-antagonist), iodophenpropit (H3R-antagonist) and JNJ7777120 (H4R-antagonist), respectively while group-VII received DMSO intramuscularly. ELISA was used to assess the immunological investigations. The SRBC-specific immunoglobulins (Igs), IgM and IgG were significantly increased (p<0.05). Hepatotoxicity due to same histamine and HRs-antagonists were demonstrated by biochemical and histopathological methods. Rabbits in group II-VI had significantly (p<0.05) elevated levels of serum enzymes (ALT, AST, ALP) and bilirubin. Histopathological examination showed maintained hepatic lobular architecture in histamine and DMSO-treated groups a kin to control. Notable findings in other groups included increased binuclearity in H1R, trinuclearity in H2R, oxyphilic clusters of hepatocytes in H3R and moderate centrilobular necrosis in H3R and H4R-antagonist-treated groups without obvious inflammatory cell infiltration and Kupffer cell prominence. It is concluded that HRs-antagonist play immune suppressive role through H1R, H2R and H4R while immune enhancing role through H3R. In addition, HRs-antagonists appear moderately hepatotoxic in terms of altered serum enzyme levels and non-inflammatory hepatocellular damage.

Dose-dependent effect of histamine on liver function markers in immunized rabbits

OBJECTIVE The present study was designed to delineate the hepatotoxicological roles of histamine dose-dependently in immunized rabbits. METHODS The cohort comprised of three groups (II, III and IV), containing 18 rabbits each, and received subcutaneous histamine 50 μg/kg, 100 μg/kg and 200 μg/kg, respectively for 10 days (b.i.d., starting from 3 days prior to immunization until 7 days after immunization). Group I (control, n=18) received subcutaneous sterile distilled water for 10 days. They were subsequently immunized at day 3 with intravenous injection of SRBC (1×10(9) cells/ml). Blood samples were collected on pre-immunization (pre-I) day 0, as well as on days 7-, 14-, 21-, 28- and 58-post-immunization (post-I). Biochemical parameters aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin [total bilirubin (TB), direct bilirubin (DB) and indirect bilirubin (IB)] were determined. RESULTS Groups II and IV revealed a significant decrease (on day 0-pre-I) and a significant increase (on days 7-, 14-, 21-, 28- and 58-post-I) in ALT and AST levels, when compared with the corresponding values of groups I and III while group II showed a significant increase in ALT and AST levels as compared to group IV. ALP levels in groups II, III and IV showed a significant enhancement when compared with group I. Moreover, results of TB, DB and IB demonstrated increased levels in group III when compared with groups I, II and IV. The results were found statistically significant (p<0.05). CONCLUSION Short-term treatment of histamine produces dose-dependent differential patterns of hepatic dysfunctions suggestive mild liver degeneration warranting further long-term studies.

Biochemical and histopathological evaluation of histamine receptors (H1R, H2R, H3R and H4R)-agonist in rabbits

The present study was designed to investigate the biochemical and histopathological changes in the livers of rabbits treated with histamine and histamine receptors (H1R-H4R)-agonist. The cohort comprised of six groups containing five rabbits each. Control group received sterile distilled water (1 mL/kg × b.i.d.) and treated groups received subcutaneous histamine (100 μg/kg × b.i.d.) and H1R-H4R-agonist (histamine trifluoro-methyl toluidide, amthamine, R-[-]-α-methylhistamine, clobenpropit, respectively) each in a dose of 10 μg/kg × b.i.d. (12 h [8 am and 8 pm]) for 30 days. Hepatotoxicity due to these agonists was analyzed using biochemical and histopathological methods. Histamine and H1R-H3R-agonist were found to be hepatotoxic as shown by statistically significant (p < 0.05) elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), most marked in the H3R-agonist group. However, their levels in H4R-agonist group remained very similar to the control group. The entire drug treated groups as compared to control showed significant elevated levels of alkaline phosphatase (ALP). Histopathological examination revealed obvious changes in histamine, H2R- and H3R-agonist groups in terms of alteration of hepatic microstructure, congestion, focal necrosis and increased incidence of multinucleate hepatocytes while H1R and H4R groups showed minimal changes. From the findings of the present study it may be concluded that on repeated administration, histamine and HR-agonists-induced hepatotoxicity which is most pronounced with H3R-agonist though not severe enough to jeopardize the vital functions of liver and warrants further long-term studies.

An Overview of Histamine Synthesis, Regulation and Metabolism, and its Clinical Aspects in Biological System

Histamine is an autacoid widespread in plant and animal kingdoms. In the early 1900s, it was identified as a mediator of biological functions by Sir Henry Dale and co-workers and drugs targeting histamine receptors have been in clinical use for more than 60 years. The synthesis of histamine was discovered by Windausa and Vogta in 1907. Its synthesis, regulation and metabolism causes numerous biological effects. This chapter will provide an overview of histamine synthesis, regulation and metabolism, and the biological effects thereof.

Immune Regulation by Various Facets of Histamine in Immunomodulation and Allergic Disorders

Histamine has tremendous biological role, mediated by four types of histamine receptors (H1R–H4R) on secretion by effector cells (mast cells and basophils) through various immunological and non-immunological stimuli. Their patho-physiological implication in all facets of biomedical areas have been reported extensively. It shows proinflammatory or anti-inflammatory effects, depending on the predominance of the types of histamine receptors. It had proinflammatory activity through the H1R, and is involved in the development of various aspects of antigen-specific immune response including the maturation of dendritic cells and the modulation of the balance of type 1 helper (Th1) T cells and type 2 helper (Th2) T cells. Histamine blocks humoral immune responses by means of a specific mechanism in which it induces an increase in the proliferation of Th1 cells and in the production of interferon-γ. Histamine stimulates the release of proinflammatory cytokines and lysosomal enzymes from human macrophages and shows the capacity to influence the activity of immune cells including mast cells, basophils, eosinophils, fibroblasts, lymphocytes, neutrophils, epithelial and endothelial cells, and plays a pivotal role in allergic inflammation which is a complex network of cellular events and involves redundant mediators and signals. In this chapter, we tried to elaborate the newer discoveries of histamine H1–H4-receptors in immunomodulation and allergic conditions, and effect of histamine in immune cells with respect to allergic diseases. We hope that this article would stimulate discussions and active research on this important aspect.

Effects of Histamine H1R-H4R-agonist on the Airway Epithelium of Rabbits

Objective: To explore the exact role of histamine receptors in respiratory system. Methods: The cohort comprised of six groups (group Ⅰ control and group Ⅱ-Ⅵ treated) containing five rabbits in each group. Control-group received vehicle (sterile distilled water) and treated groups received subcutaneous histamine (100 μg/kg, b.i,d.). and H1R-agonist (HTMT). H2R-agonist (amthamine), H3R-agonist (R-(-)-α-methylhistamine) and H4R-agoniat (clobenpropit) each in a dose of 10 μg/kg. b.i.d. for 30 subsequent days. After completion of treatment, animals were euthanized and perfused with 10% buffered formalin. Small tissue blocks of trachea and lungs were processed for paraffin embedding. Observations were recorded in sample photomicrographs taken from 10μm thick. Haematoxylin and eosin stained sections. Results: It was observed that trachea and bronchi from histamine, H1H and H4R groups had only patches of hyperplastic and hypertrophied epithelium and in general, cells in the affected region were taller heaped up. The bronchiolar epithelia from all treated groups showed hypertrophy and hyperplasia throughout with most of the cells having rounded profile and appeared to bud out from the basal cells. Conclusions: It is concluded that histamine receptors on induction via its specific agonist can induce hypertrophy, hyperplasia of respiratory tract epithelia suggesting its role akin to growth stimulating factor and warranting further long-term study.

In vivo immunomodulatory profile of histamine receptors (H1, H2, H3 and H4): a comparative antagonists study

Objective: To delineate the comparative immunomodulatory roles of H1R-H4R in antibody generation profile in rabbit model. Methods: The cohort comprised of eight groups containing 18 (9 male and 9 female) rabbits in each group. Group I remained non-immunized and received only vehicle (sterile distilled water, 1 mL/kg×b.i.d.) intramuscularly. Group Ⅱ received vehicle (1 mL/kg×b.i.d.) while Groups Ⅲ-VII (drugs-treated) received subcutaneous histamine (100 μg/kg×b.i.d.), and intramuscular H1R-antagonist (pheniramine, 10 mg/kg×b.i.d.), H2R-antagonist (ranitidine, 10 mg/kg×b.i.d.), H3R-antagonist (iodophenpropit, 1 μg/kg×b.i.d.) and H4R-antagonist (JNJ 7777120, 10 μg/kg×b.i.d.), and Group Ⅷ DMSO (1 mL/kg× b.i.d.), respectively for 10 days (starting from day 1). They were subsequently immunized with intravenous injection of sheep red blood cells (SRBC) at day 3. The estimation of serum Igs, IgM and IgG were done by ELISA, and observed at day 0 (pre-immunization), and 7, 14, 21, 28 and 58 (post-immunization). Results: It was shown that histamine and HRs-antagonists could influence a detectable antibody response to SRBC as early as day 7-post-immunization (post-Ⅰ), which lasted until day 58 post-Ⅰ. The results were found statistically significant (P＜0.05). Conclusions: This study suggests that histamine receptors play important roles in modulation of antibody generation in which H1R, H2R and H4R have immunosuppressive roles and conversely, H3R playes an immune enhancing role. The findings of this study may have clinical significance and provide the baseline information for future study.