Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant pattern: comparison of rush and conventional immunotherapy.

BACKGROUND: The mechanism of immunotherapy is unclear. Allergic disease is known to involve enhanced TH-2 cytokine responses to allergen. OBJECTIVE: In order to investigate the mechanisms of immunotherapy, we have examined changes in cytokine secretion before (13 patients) and during (nine patients) both rush and conventional venom immunotherapy (VIT) in bee venom allergic patients. METHODS: Peripheral blood mononuclear cells were stimulated in vitro with bee venom, non-specific antigen or mitogen and secretion of IL-4 (TH-2) and IFN gamma (TH-1) over the culture period measured. RESULTS: Untreated patients had TH-2 responses to venom and TH-1 responses to antigen and strong proliferative responses to venom. Controls showed no response (proliferation or cytokines) to venom and the normal TH-1 response to antigen. VIT resulted in marked changes in cytokine secretion to venom, with reduction of the abnormal TH-2 response and induction of a TH-1 response. The pattern differed in rush and conventional VIT. One day after rush VIT there was a significant fall in IL-4 secretion (P < 0.01), which rose by 3 weeks then declined. In conventional VIT there was a gradual reduction of IL-4 production significant after 2 months and undetectable by 6 months. IFN gamma secretion was induced by VIT. Proliferative responses mirrored the IL-4 changes. One day after rush VIT there was a loss of T cells, monocytes and NK cells from peripheral blood. CONCLUSION: This study shows that immunotherapy shifted cytokine responses to allergen from a TH-2 to a TH-1 dominant pattern, suggesting direct effects on T cells. How these cytokine changes relate to clinical desensitization is not clear. In the longer term they would result in an isotype switch from IgE to IgG. Early changes in cytokine or chemokine production might downregulate mast cell or basophil reactivity and explain the rapid desensitization in rush VIT.

Effects of selenium supplementation on immune parameters in gut failure patients on home parenteral nutrition.

The relationships between some parameters of the immune response and selenium were investigated in five patients receiving home parenteral nutrition for short-bowel syndrome. They were first submitted to a relative depletion by providing 20 micrograms selenium/day as L-selenomethionine for 1 mo. Then, daily selenium intake was raised to 200 micrograms for 2-4 mo. On entering the study, the patients presented a relatively good health status, and immunological parameters were at the lowest limit of the normal range. Four patients rapidly responded to the 200-micrograms supplementation by a continuous increase in their plasma selenium levels, whereas the fifth patient showed a moderate and late increase. At the end of the trial, there was an improvement in the lymphocyte response to pokeweed and phytohemagglutinin mitogens in four patients and to CD3 in three patients. The response to two of three antigens (Candidin, Varidase) tested was also enhanced in the same patients, but the response to the third antigen (tetanus toxoid) was uniformly low in all patients. The only patient showing essentially no immune improvement after selenium supplementation was the one with a low and delayed increase in plasma selenium. This study supports a role for selenium in the maintenance of an optimal immune response in humans.

A comparative study of ciprofloxacin and conventional therapy in the treatment of patients with chronic lower leg ulcers infected with Pseudomonas aeruginosa or other gram-negative rods.

Twenty-six elderly patients with chronic leg ulcers infected by Pseudomonas aeruginosa or other aerobic Gram-negative rods were randomised to two treatment groups. The control group (eight patients) received conventional local therapy and the other group (18 patients) was treated with oral ciprofloxacin for three months in addition to conventional local therapy. In the beginning of the study both groups were comparable with the age of the patients and the associated diseases including impairment of arterial and venous circulation in the lower legs. Also the size, duration and the severity of the inflammation reaction in the leg ulcers were comparable before the start of the therapy. Ciprofloxacin was clinically more effective than the standard therapy in reducing the size of the ulcer (p less than 0.05). Also the need of extra systemic antibiotics decreased significantly in the ciprofloxacin group compared with the controls. In three out of eighteen ciprofloxacin treated patients the leg ulcers disappeared completely during the three months' study period compared with none in the control group. However, ciprofloxacin resistant strains, mainly staphylococci, appeared in the leg ulcers in 67% of the ciprofloxacin treated patients compared with 0% in the control group (p less than 0.01). No significant side-effects due to ciprofloxacin except the resistant strains were noticed. We conclude that oral long-term ciprofloxacin therapy is effective in the treatment of chronic leg ulcer infections due to Gram-negative rods but selection of ciprofloxacin resistant strains is a problem in this patient group.

[Hodgkin's disease: study of delayed hypersensitivity of 64 non treated patients. Value of epicutaneous test using croton oil]. / Maladie de Hodgkin: étude de l'hypersensibilité retardée de 64 malades non traités. Intérêt du test épicutané à l'huile de croton

Cellular immunity in 64 patients with Hodgkin's disease was studied during diagnosis before any treatment. The functional deficiency of the thymodependent lymphocyte was demonstrated in vivo by skin tests and, in vitro, by the test of inhibition of leucocyte migration to phytohemagglutininin and spontaneous rosette formation, to sheep red cells. This deficiency correlates with the clinical spread and the histological severity. The relationship between skin anergy and biological tests was found. The epicutaneous test using croton oil possesses non-specific inflammatory activity. It is negative this test is negative, skin reactivity to specific antigens is reduced. The croton tests help interpretation of skin responses to specific antigens and thus assessment of the immune state.

Serum immunoglobulin, dermal response, and lymphocyte transformation studies in horses with chronic diarrhea.

Serum specimens from 12 sick and 20 normal horses were examined for levels of different classes of immunoglobulin (Ig) by a single radial immunodiffusion. The level of IgA in the sera of sick horses was about 50% lower than in the sera of normal horses. By contrast, the level of serum IgG was higher in sick than in normal horses. Phytohemagglutinin (PHA) responsiveness of blood lymphocytes showed transient suppression during the stage of severe diarrhea. The regaining of PHA responsiveness of lymphocytes was observed simultaneously with the recovery process. However, the responsiveness of lymphocytes in recovered horses was still markedly lower than in normal horses. Allergic reactions in sick and normal horses were studied by observing dermal response to the injections of saline extracts from some of the horse feeds. A delayed hypersensitivity reaction to streptokinase-streptodornase and PHA was also studied. The allergic reactions to these extracts were not induced in either sick or normal horses; however, inflammatory response to the extracts was about 50% greater in normal than sick horses. Response to the intradermal injection, either streptokinase-streptodornase or PHA, was significantly greater in normal horses than sick horses. These findings are discussed with respect to the pathogenesis of chronic diarrhea and the complexity of immunodeficiency demonstrated in this disease. The possibility that transient defects of cell-mediated immunity may predispose to chronic diarrhea is proposed.

Proteolytic enzymes as adjuncts to antimicrobial prophylaxis of contaminated wounds.

When a tissue is injured, its vessels exhibit a marked increase in vascular permeability. Blood proteins, including fibrinogen, traverse the vessel walls and lead to the development of a surface coagulum. This inflammatory response continues until primary closure of the wound edges is accomplished. The thickness of the surface coagulum is roughly proportional to the time interval between wounding and closure. This coagulum encompasses the surface contaminants, preventing contact with either topical or systemic antibiotics. The presence of this surface coagulum limits the time in which antibiotic prophylaxis is effective. At three hours after injury, antimicrobial prophylaxis of contaminated wounds has no therapeutic value. Hydrolysis of the protein coagulum by proteolytic enzymes enhances the activity of the antibiotic in experimental wounds. The success of proteolytic enzymes as adjuncts to delayed antibiotic treatment can be correlated with the clot lysis activity of the enzymes in vitro. Travase, the most potent fibrinolytic enzyme, is the most effective adjunct to delayed antibiotic therapy of contaminated wounds. In contrast, the active enzymes found in Elase, which exhibit no significant clot lysis activity in vitro, do not potentiate the activity of antibiotics in wounds subjected to a delay in treatment. Travase prolongs the period of effective topical antibiotic action for at least eight hours in experimental contaminated wounds. The therapeutic merit of Travase is also apparent when the antibiotic is administered systemically. Travase shows promise as an adjunct to a variety of antibiotics that are effective against both gram-positive and gram-negative organisms. The results of these experimental studies support our belief that clinical studies support our belief that clinical studies should now be initiated to test the therapeutic value of Travase as an adjunct to antibiotics in heavily contaminated wounds subjected to an unavoidable delay in treatment.

The diagnostic and prognostic significance of delayed hypersensitivity skin testing in patients with urological cancer.

The responses to several skin test antigens of patients with bladder or prostatic cancer has been compared with responses of normal controls. All of the controls and all of the patients with prostatic cancer (irrespective of the stage of the tumour or the method of treatment) showed responses to dinitrochlorbenzene. 80% of all patients with bladder cancer responded to DNCB, but a highly significant number of patients with advanced disease showed no response. This test appears especially useful in predicting the prognosis in patients with bladder tumours and its routine use is recommended. Response to candida extract, streptokinase/streptodornase (SKSD) and purified protein derivative (PPD) were also studied. No conclusion could be drawn as to their value as a prognostic index.

Cellular immunity in vitro. Clonal proliferation of antigen-stimulated lymphocytes.

When sensitive lymphocytes are cultured with the appropriate antigen, lymphoblasts appear after 24-48 hr of incubation and the number of these increases steadily from the 2nd to the 6th or 7th day. Our problem was to discover, at a cellular level, how this increase takes place; whether it is a massive response of many cells, stepwise recruitment of cells into the lymphoblast class, or simply repeated division of a few cells to form clones. In these experiments lymphocytes were incubated with antigen in culture tubes for 2-4 days and then a few cells, usually less than 200, were transferred to special microchambers for further culture. In these microchambers the cells could be viewed continually with a microscope and their fate recorded over the next 3-5 days by time-lapse cinemicrography. Examination of the film produced in this way showed that lymphoblasts divided and redivided to produce clones of 64 cells or more. It was possible to measure generation times from the film for 301 cells; the majority were between 8 and 13 hr but the range was 7.5-38.0 hr. There was no clear difference between generation times of human lymphocytes stimulated with tuberculin, streptokinase-streptodrnase, extract of the American pokeweed, or in the mixed leukocyte reaction. Similar times were also found for rat cells in the mixed leukocyte reaction. While these observations show that clonal proliferation does occur and could reasonably account for all the increase of lymphoblasts in lymphocyte cultures, the experiments, because of their design, do not exclude the possibility that other mechanisms such as recruitment may play a role as well, particularly during the first 48 hr after contact between sensitive cells and antigens.