Immunostimulatory Drug Research Articles

Immunotherapy and other novel therapies

Although no true breakthroughs occurred, publications during the 12-month period of this review added substantial definition to certain novel immunotherapies potentially applicable to the treatment of rheumatoid arthritis. Overall, this period witnessed maturation in the field of biologic interventions. Clinical trials provided further data needed to assess the efficacy of high-dose intravenous gamma-globulin therapy in patients with systemic juvenile rheumatoid arthritis, and extended uncontrolled experience with interferon-gamma in adult rheumatoid arthritis was obtained. An intriguing immunostimulant and antiviral drug, isoprinosine (inosine pranobex), failed in a scientifically rigorous trial in rheumatoid arthritis. Provocative insights into totally new approaches surfaced in additional reports from a variety of immunologic areas. Although seemingly distal to rheumatoid arthritis, these papers are cited because their further development or adaptations could reach a stage where clinical trials in rheumatoid arthritis are warranted.

The effect of immunostimulatory drugs on sulfhydryl compounds in plasma, liver and brain after ethanol-induced liver injury in rats

Sulfhydryl compounds in plasma, liver and brain of rats treated with two immunostimulant drugs, isoprinosine and levamisole, after alcoholic liver injury have been investigated. After use of both drugs for 6 days we found partially beneficial effect on the SH-groups in plasma and liver. No changes in nonprotein SH compounds were observed in rat brain after treatment with isoprinosine, levamisole or ethanol. Furthermore, levamisole shortens the time necessary for the return of AlAT activity to normal value.

Simple high-performance liquid chromatographic method for the determination of PGT/1A, a new immunostimulating drug, in biological fluids

This paper describes a simple high-performance liquid chromatographic method for the determination of PGT/1A (3-L-pyroglutamyl-L-thiazolidine-4-carboxylic acid), a new immunostimulating drug, in plasma and urine. The column was packed with LiChrospher-NH2 (5 microns), the mobile phase was 0.02 M monobasic potassium phosphate (pH 3.2 with concentrated phosphoric acid)-acetonitrile (25:75, v/v), the flow-rate was 1.2 ml/min, the detection wavelength was 210 nm and the apparatus was a Varian Model 5000. Plasma (1 ml) was added to 1.2 ml of acetonitrile and the supernatant injected; the urine was diluted 1:5. The retention time of PGT/1A was 9.4 min in plasma and 9.9 min in urine. The method was validated for recovery, accuracy and reproducibility. The results after intravenous injection in twelve volunteers are also given.

Treatment with interferon of chronic hepatitis B associated with antibody to hepatitis B e antigen

Persistence of HBV replication (serum HBV-DNA and intrahepatic HBcAg) and markers of HBV-induced (IgM anti-HBc positive) liver disease in anti-HBe-positive patients characterize a peculiar form of chronic hepatitis B. This form of hepatitis B prevails in the Mediterranean Basin, Middle and Far East and is associated with the infection of an HBV variant that lacks the capacity to produce HBeAg. We analysed the results of interferon treatment of 90 patients with chronic anti-HBe-positive hepatitis included in four randomized controlled trials. Interferon inhibited viral replication to undetectable levels and ALT normalized in about 70% of patients. However, the effect was transient in the majority of cases and hepatitis B relapsed in 41 to 90% of patients. A discrepancy in the rate of relapses could be explained by a significant difference in patients populations with a higher prevalence of cirrhotic patients in studies with poorer response. Therefore, in advanced anti-HBe-positive chronic hepatitis B, interferon shows a lower efficacy than in HBeAg-positive patients. The earlier treatment starts, the more efficacious is the response to interferon. Future clinical trials should focus on higher doses for longer periods, repeated courses or on combination therapy with nucleoside analogs or immuno-stimulant drugs.

Preventive effects of an immunostimulating product on recurrent infections of chronic bronchitis in the elderly

The effect of an immunostimulating drug, OM-85 BV, was demonstrated on recurrent infection rates in 265 elderly patients with a defined state of chronic bronchitis, during a 6-month, double-blind, placebo-controlled trial. Patients receiving OM-85 BV presented less infections (p = 0.005) and a significantly reduced intake of antibiotics (p = 0.02) as compared to those receiving a placebo and the antibiotic intake was significantly reduced (p = 0.02).

Munopharmacological studies on PGT/1A, a new immunostimulating drug

Munopharmacological studies on PGT/1A, a new immunostimulating drug

Experimental studies on PGT/1A, a new immunostimulating drug

Experimental studies on PGT/1A, a new immunostimulating drug

Minireview Murine models for Acquired Immune Deficiency Syndrome

The mouse has been suggested as a host for comparative studies of several aspects of Human Acquired Immune Deficiency Syndrome (AIDS). Models include studies where part or all of the genome of Human Immunodeficiency Virus (HIV) has been incorporated into murine DNA in living mice. However, the most promising oppurtunities for study of immunological changes, vaccine development, cofactor involvement in disease, and anti-retroviral and immunostimulatory drug testing involve infection with murine retroviruses which cause many functional changes similar to AIDS. The viruses' effects on immune systems are reviewed with special emphasis on LP-BM5 murine leukemia virus which infects T and B cells, and macrophages. LP-BM5 infection suppresses cell functions while causing polyclonal lymphocyte activation. Murine immunological characterization, availability of inbred mouse strains, economy of using mice versus primates or humans models, and similarity of immune change caused by murine retroviruses compared to those seen in AIDS caused by HIV encourage rapid development of the LP-BM5 murine leukemia model.

Intralymphatic Interleukin 2 Treatment in Patients with Acquired Immunodeficiency Syndrome: Preliminary Experience in Three Cases

Patients with opportunistic infections during the course of acquired immunodeficiency syndrome (AIDS) were analyzed for cellular immune functions and found to be severely immunocompromised. In particular, interleukin 2 (IL 2) production appeared to be defect not only qualitatively but also quantitatively. In some of these patients, exogenous IL 2 improved immune response in vitro. Intralymphatically administered highly purified natural IL 2 was given repeatedly (over a time period of ten days) to three of these patients. In two cases, such a treatment course was repeated later. Clinical response - at least in some patients - appeared to be of temporary benefit. Shortly after termination of IL 2 application in two patients an increase of lectin responsiveness as well as improved reactivity in skin testing was noted, encouraging further exploration of IL 2 as an immunostimulatory drug in AIDS patients.

Chemotherapeutics: A questionable or a promising project

While repository adjuvants are already established drugs for antigen specific immunomodulation, no unspecific active immunomodulator has successfully passed clinical trials in tumor patients in Western countries yet. As this is in striking contrast to the effects seen with unspecific immunomodulators in experimental immunological and tumor test systems, the value of those screening models to predict clinical success may be asked for. To improve the success rate, it is recommended to test compounds for their immunomodulatory effects as broad as possible in ex vivo and in vivo test systems. Subsequently, the prophylactic as well as therapeutic potency of selected immunomodulating drugs should be evaluated in various models of aptitude, such as chronic infection, autoimmune diseases and chronic inflammatory reactions. Those diseases are at least to a certain extent influenced by the immune system, in contrast to the uncertainty in case of tumor diseases. In a battery of chronic infection models we could find that different chemo-immunotherapeutics with very similar immunopharmacological activity behaved quite different. Most compounds were ineffective, a part enhanced chronic diseases and only in a few cases a therapeutic effect could be shown. On the other hand, effectivity in protection against the pathogenicity of subsequently applied, selected microorganisms does not predict the therapeutic potency for the same pathogen. Altogether the data show that activation of cells of the immune system by an immunostimulating drug does not predict its therapeutic potency. Moreover, activation of immune cells may also impair the immune resistance.

Pharmacology of macrophages and related cells: Immunostimulant drugs targeted by monoclonal antibodies and neoglycoproteins

Pharmacology of macrophages and related cells: Immunostimulant drugs targeted by monoclonal antibodies and neoglycoproteins

Immunostimulation. Clinical and experimental perspectives.

Three classes of immunostimulating drugs are described, each representing a different approach to the problem of pharmacological immunostimulation. The rationale for the use of microbes or microbial agents as immunostimulators rests on the fact that some micro-organisms, especially those that replicate intracellularly, carry a special potential to activate macrophages. Clinically, the use of these agents in patients with tumors and infections has been disappointing; however, there have been positive exceptions like the responsiveness of melanomas and bladder carcinomas to the injection of BCG. Many of the inconclusive results may be due to insecurities in the dosage of microbial preparations and to a general lack in standardization. Some structures with high efficacy and low toxicity which have recently evolved from this field deserve further investigation. A number of structurally unrelated synthetic compounds was found to influence immune parameters. Levamisole can today be classified as an immunostimulating drug with limited utility in recurring infections and in chronic polyarthritis. Several immunostimulating drugs which have attracted interest contain a purine as the effective component. This is not surprising in view of the fact that many genetically determined immunodeficiencies can be traced to defects of enzymes which play a crucial role in purine biosynthesis. Finally, the potential role of lymphokines as stimulators of the immunosystem is briefly described. Some of these glycoproteins have recently become available for clinical trials. Others will be made available through genetic engineering. The therapeutic utility of these compounds is not yet clear; they will, however, be of great value as probes for the study of immune functions and for the development of immunopharmacology.

Correction of an in vitro immunoregulatory defect in atopic subjects by the immunostimulating drug fanetizole mesylate (CP-48,810)

The effect of Fanetizole mesylate or CP-48,810, a new immunostimulating drug, on suppressor cell function and IgE synthesis in vitro was evaluated in atopic patients with allergic rhinitis and/or asthma and eczema. In the absence of the drug, histamine (10 −3M) stimulated blood mononuclear cells from 23 atopic patients suppressed concanavalin A-induced lymphocyte proliferation by a mean (±S.E.M.) of 9.3%±3.5 (compared to 25.1%±2.7 for histamine stimulated mononuclear cells from non-atopic controls). The addition of the drug (2.5 × 10 −4M) in vitro significantly increased histamine suppressor cell activity of atopic patients to 26.6%±3.9 (compared to 24.7%±2.8 for control cells in the presence of the drug). In order to determine a possible mechanism through which CP-48,810 might enhance histamine-induced suppressor activity, we examined the effects of the drug on the production of histamine-induced suppressor factor (HSF) by lymphocytes and the production of prostaglandin E 2 by blood monocytes in the presence of HSF. Supernatants generated from histamine (10 −4M) stimulated patient lymphocytes caused a 9.0% ± 1.8 suppression of concanavalin A-induced lymphocyte proliferation (compared to 25.0%±3.1 caused by supernatants from normal subjects). If the drug (2.5 × 10 −4M) was added at the beginning of culture, HSF activity in supernatants derived from atopic lymphocytes increased significantly to 20.2%±1.8 (compared to 23.3%±3.9 for drug treated control supernatants). Prostaglandin E 2 production by atopic monocytes exposed to HSF was less than that of normal monocytes in the absence of the drug. The addition of CP-48,810 decreased both basal and HSF-augmented PGE 2 production by both control and atopic cells. Therefore, we could not evaluate this component of the suppressor response further. IgE synthesis in vitro was evaluated in the presence or absence of CP-48,810. B cells from 16 atopic subjects without eczema produced a mean (±S.E.M.) of 516±149 pg/10 6 cells of IgE in the absence of the drug. In the presence of 2.5 × 10 −4M drug, IgE synthesis was reduced to 196± 70 pg/10 6 cells (68.4% suppression). Blood mononuclear cells from 6 atopic subjects with eczema synthesized a mean (±S.E.M.) 1984±531 pg/10 6 cells of IgE in the absence of the drug. In the presence of 2.5 × 10 −4M drug, IgE synthesis was reduced to 1486±406 pg/10 6 cells (32.3% suppression). The differing amounts of suppression of IgE synthesis caused by the drug could result either from the greater amount of IgE produced by atopic eczema patients (more difficult to suppress) and/or differing severity of suppressor cell defect in the latter patients. Of note, CP-48,810 did not significantly alter pokeweed-induced IgG synthesis by atopic and control cells. These results suggest that CP-48,810 can partially correct an immunoregulatory defect in atopic subjects, and associated with this finding is a reduction in de novo total IgE synthesis. These findings describe a new potential use for CP-48,810 and in vivo studies appear to be warranted.

Levamisole induced enhancement of polymorphonuclear leukocyte migration in patients with periodontitis.

The effect of the immunostimulatory drug levamisole on the stimulated migration of polymorphonuclear leukocytes (PMNs) from patients with periodontitis and from normal subjects was assessed. Because of previous conflicting reports on the effect of this drug on PMN chemotaxis, the conditions of the assay were first investigated using zymosan‐activated serum (ZAS) as a chemoattractant. When PMNs were suspended in a medium containing 2% bovine serum albumin and stimulated with 10% ZAS, no enhancement was observed. In contrast, levamisole had a substantial enhancing effect when the PMNs were suspended in protein‐free medium and stimulated with a 25% concentration of ZAS. Using conditions between these extremes, the effect of levamisole on the migration of PMNs from live patients with periodontitis and from a sibling of one of the above who had severe recurrent otitis media was studied. PMN migration was depressed in all of the patients; the mean value was 23.3±4.9% of normal, range 2.0–53.0%. Adding levamisole enhanced cell migration in all cases; the average enhancement for the group was 297.5±46.8% p < 0.005), range 56.0–769.0%. Enhancement was maximal at drug concentrations between 0.1 and 1 mM. Levarnisole also enhanced the migration of PMNs from some but not all normal subjects, but to a lesser degree; mean enhancement was 58.4±23.8%, range 0–136.0%. Thus, under the assay conditions used, levamisole enhanced and in part corrected the depressed migratory responsiveness of PMNs from these patients with periodontitis.

204 Correction of an in vitro immunoregulatory defect in atopic subjects by the immunostimulating drug fanetizole mesylate (CP-48, 810)

204 Correction of an in vitro immunoregulatory defect in atopic subjects by the immunostimulating drug fanetizole mesylate (CP-48, 810)

Depressed neutrophil motility in patients with recurrent herpes simplex virus infections: in vitro restoration with levamisole.

The random migration and chemotaxis of neutrophils from 10 patients with recurrent infections with herpes simplex virus were assessed. Chemotaxis to endotoxin-activated serum was markedly diminished in this group, but random migration was only mildly reduced, and chemotaxis to hydrolyzed casein was normal. The effects of the immunostimulant drug levamisole on the chemotaxis of neutrophils were assessed both in vitro and in patients after 150 mg of the drug was taken daily for three days. The defective chemotactic response could be corrected in vitro by treatment of the neutrophils with 10(-3) M levamisole. Of 10 patients treated with levamisole, five showed improved chemotaxis after three days, but no improvement in neutrophil function was observed in the other patients.

Subversive activity of syngeneic tumor cells as an escape mechanism from immune surveillance and the role of prostaglandins.

Mice bearing a syngeneic tumor become increasingly immunodepressed during growth of the tumor, being unable to develop both cellular and humoral immunity to a histoincompatible tumor allograft and to reject the allograft. This failure to reject a strongly antigenic tumor allograft suggests that immunodepression associated with growth of a weakly antigenic syngeneic tumor provides the syngeneic tumor with an escape mechanism. This immunodepression is also manifest by the suppression of the response of spleen cells to mitogen stimulation by syngeneic tumor cells, both in vivo and in vitro. T cells that are stimulated by PHA, a T-cell mitogen, are the primary targets, and their suppression is the result of the direct subversive activity of the tumor cells. Subversion of T cells by tumor cells seems to be mediated through the prostaglandin pathway, because the prostaglandin PGE2 is itself suppressive, and an antagonist of PGE2 and an inhibitor of prostaglandin synthetases both inhibit the subversive activity of tumor cells. Several tumor cell lines tested, of different etiology and histologic type, all were subversive. This suggests that this subversive activity may be a general property of tumor cells and may be a key element in their ability to thwart the immunological system of the host. For this reason, any therapeutic regimen of cancer, based on immunostimulating drugs, should include drugs that can inhibit active subversion of the immune system by the tumor itself. Antagonists of prostaglandins and inhibitors of prostaglandin synthetases show promise in this regard.

Experimental immunosuppression induced by herpes simplex virus

Cell-mediated immune response was studied in experimental herpetic infection in mice. Our data suggest that herpes simplex virus induced immunosuppression in mice. This depression was documented by the unresponsiveness of the lymphocytes to PHA stimulation in vitro and by the enhanced susceptibility of adult mice to Coxsackie B virus infection. Our data also suggest that levamisole, a potent immunostimulant drug, had no effect on the unresponsiveness of the lymphocytes to PHA stimulation.