The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures.

Thalidomide is an effective immunomodulatory drug in man, but its mechanism of action remains unclear. We hypothesized that, in addition to its reported inhibitory effects on production of monocyte-derived tumour necrosis factor-alpha (TNF-alpha), thalidomide might be effective at the level of Th immunoregulation. In a comparative study with the immunosuppressant cyclosporin A, we have demonstrated a potent and specific effect of thalidomide on cytokine production relating to the distinct Th1 and Th2 subsets. It induced and enhanced the production of IL-4 and IL-5 and, at the same dose (1000 ng/ml), significantly inhibited interferon-gamma (IFN-gamma) production in phytohaemagglutinin (PHA)-stimulated human peripheral blood mononuclear cell (PBMC) cultures. Stimulation of PBMC with recall antigen (streptokinase:streptodornase (SKSD)) at 144 h in the absence of thalidomide resulted in a predominantly Th1 response, with the production of IFN-gamma and IL-2. Thalidomide switched this response from a Th1 to a Th2 type. The effect was most pronounced at 1000 ng/ml thalidomide, where inhibition of IFN-gamma and enhancement of IL-4 production was maximal. In unstimulated cultures thalidomide alone induced IL-4 production. Cyclosporin A, in contrast, inhibited both Th1 and Th2 cytokine production by PHA-stimulated PBMC. Time course data from thalidomide-treated cultures revealed that the augmented IL-4 production diminished as the culture time increased, whereas IFN-gamma production was significantly increased. This response might be due to activation-induced apoptosis of Th2 cells or the induction of Th2 cell anergy, in the continued presence of stimulating agents, with the emergence of IFN-gamma-secreting Th1 cells when Th2 antagonism declines. The effects of thalidomide and related compounds may enhance our understanding of the mechanisms of T helper cell selection, offer the possibility of controlled therapeutic switching between Th1 and Th2 responses, and may lead to a rational approach for the treatment of some T cell-mediated immunological disorders.     

Antigenic properties of HpaA and Omp18, two outer membrane proteins of Helicobacter pylori

Outer membrane proteins (OMPs) are incorporated into the outer plasma membrane of Helicobacter pylori and are important for, e.g., ion transport, adherence, structural and osmotic stability, and bacterial virulence but may also be antigenic due to their surface exposure. Previous proteome-based approaches with H. pylori lysates determined a strong serological reaction towards two H. pylori OMPs, HpaA (TIGR HP0797) and Omp18 (TIGR HP1125). PCR was used to detect DNA encoding the two proteins, and a positive signal was found in all H. pylori strains tested. Proteins were cloned and expressed in the human kidney cell line HK293 with the QiaExpressionist system with a C-terminal His tag. Only sera from infected persons showed a positive reaction with the recombinant proteins. Recombinant HpaA (rHpaA) and rOmp18 were incubated with human peripheral blood mononuclear cells and induced secretion of interleukin-12 (IL-12) and IL-10 from these cells. To determine the effect on antigen-presenting cells, human blood monocytic and dendritic cells (DCs) were isolated by magnetic cell separation. rOmp18 and rHpaA strongly stimulated major histocompatibility class II and CD83 expression 7- to 10-fold on isolated DCs. rHpaA and rOmp18 failed to stimulate IL-8 secretion from monocytes but increased secretion of IL-12 and IL-10 from DCs significantly. In summary, HpaA and Omp18 are recognized by human dendritic cells and induce their maturation as well as antigen presentation. HpaA and Omp18 of H. pylori thereby appear to have a specific antigenic potential in humans.     

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation.

More than 40000 hematopoietic cell transplants (HCTs) are performed worldwide each year. With improvements in transplant technology, larger numbers of transplant recipients survive free of the disease for which they were transplanted. However, there are late complications that can cause substantial morbidity. Many survivors are no longer under the care of transplant centers, and many community health care providers may be unfamiliar with health matters relevant to HCT. The Center for International Blood and Marrow Transplant Research (CIBMTR), European Group for Blood and Marrow Transplantation (EBMT), and American Society for Bone Marrow Transplantation (ASBMT) have developed these recommendations to offer care providers suggested screening and prevention practices for autologous and allogeneic HCT survivors.     

Corticosterone influences on Mammalian neonatal sensitive-period learning

Infant rats exhibit sensitive-period odor learning characterized by olfactory bulb neural changes and odor preference acquisitions critical for survival. This sensitive period is coincident with low endogenous corticosterone (CORT) levels and stress hyporesponsivity. The authors hypothesized that low corticosterone levels modulate sensitive-period learning. They assessed the effects of manipulating CORT levels by increasing and removing CORT during (Postnatal Day 8) and after (Postnatal Day 12) the sensitive period. Results show that (a) exogenous CORT prematurely ends sensitive-period odor-shock-induced preferences; (b) adrenalectomy developmentally extends the sensitive period as indicated by odor-shock-induced odor-preference learning in older pups, whereas CORT replacement can reinstate fear learning; and (c) CORT manipulation modulates olfactory bulb correlates of sensitive-period odor learning in a manner consistent with behavior.     

Filling the gaps in physician communication. The role of the Internet among primary care patients

BACKGROUND: Millions of people use the Internet as a source for health information yet little is understood about how the use of the Internet for health information is related to the doctor-patient relationship. OBJECTIVE: We conducted the present study to understand the association between one's interest in using the Internet for general and quality-oriented health information and attitudes about one's communications with health care provider(s). DESIGN: Cross-sectional survey. SETTING: Four community-based primary care practices in Rhode Island. MEASUREMENTS: A single self-administered survey included items to measure: interest in using the Internet to look for general and quality-oriented information and a patient's perceptions of the degree to which their doctors over the previous year have: (1) given them information and (2) engaged them in the decision-making process. RESULTS: A total of 300 patients completed the survey. Among patients without Internet access, interest in using the Internet for health related activities was less among patients who felt that their doctor gave less information: Odds ratio 0.83 (95% CI, 0.70-0.98) and greater among patients who felt that their doctor engaged them more in decision making: Odds ratio 1.3 (95% CI, 1.1-1.6). Among patients with Internet access, we found no relationship between interest in using the Internet for health related activities and measures of patient-physician communication or patient-physician decision making. CONCLUSIONS: Interest in using the Internet for health information is greater for those who (1) felt their doctors provided less information and (2) felt their doctors engaged them more in the decision-making process, but this is true only for those without access to the Internet.     

Kinetics and functional implications of Th1 and Th2 cytokine production following activation of peripheral blood mononuclear cells in primary culture

The importance of cytokine production in some disease processes is now widely recognized. To investigate temporal relationships between cytokines, we stimulated peripheral blood mononuclear cells (PBMC) in vitro using the T cell mitogen phytohemagglutinin (PHA) and various antigens chosen to induce predominantly Th1 (streptokinase: streptodornase or purified protein derivative) or Th2 (Dermatophagoides pteronyssinus, bee or wasp venom: allergens in sensitive subjects) responses. Cytokine production was measured by sensitive bioassays or enzyme-linked immunosorbent assays. Of the 30 subjects studied, 10 were normal and 20 individuals were allergic to either D. pteronyssinus (n = 10) or bee venom (n = 10) (examined before specific allergen immunotherapy). We examined the temporal profiles of a panel of cytokines produced in prmary culture. In PHA-driven cultures, cytokines were found to be sequentially produced in the order interleukin (IL)-2, IL-4, IL-5, IL-3, interferon (IFN)-γ, IL-10, IL-6, IL-12 and tumor necrosis factor (TNF)-α. The response to allergen in allergic patients was predominantly Th2 in nature, with the production of IL-4, IL-5, IL-6 and IL-10, but little or no IFN-γ. IL-2, IL-3, TNF-α and IL-12 were also produced in low amounts. The response of both atopic and normal subjects to recall bacterial antigens was predominantly Th1, with high levels of IFN-γ, IL-2 and TNF-α. The relevance of the order, amount and speed of production, characteristic kinetics (production, consumption, homeostatic regulation) and the cell source of the cytokines are discussed.     

Two sisters with Escobar syndrome

We report on 2 sisters with an autosomal-recessive multiple pterygium syndrome, type Escobar, consisting of multiple pterygia with severe contractures, short stature, and minor facial and external genital anomalies. The striking finding was severe muscular atrophy. We speculate that a neu-romuscular disorder is the underlying pathogenesis of Escobar syndrome. © 1995 Wiley-Liss, Inc.