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PubMed1992

CD4+ Th2 response induced by Schistosoma mansoni eggs develops rapidly, through an early, transient, Th0-like stage.

Data from recent studies of murine schistosomiasis mansoni have indicated that certain characteristics of this infection, such as eosinophilia and elevated IgE, are due largely to the induction of Th2-like immune responses by parasite ova. The present study was designed to examine more closely the genesis and development of these skewed Th responses to schistosome eggs. Accordingly, eggs isolated from infected mice were injected s.c. into normal mice. After inoculation, draining lymph node (LN) cells were recovered, phenotyped, and tested for their ability to proliferate and secrete IL-2 and IFN-gamma (as markers of Th1 function) and IL-4, IL-5, and IL-10 (Th2 cytokines). The results show a maximal LN enlargement of 40- to 100-fold by day 3 after egg inoculation. The CD4/CD8/B cell ratio at this time is similar to that in LN from normal mice, but increases in numbers of cells expressing very low levels of MEL-14 and high levels of Pgp-1 are evident by days 3 and 10, respectively. Surprisingly, the initial detectable Ag-specific response to schistosome eggs, observed at day 1, is the production of IFN-gamma. By day 3, LN cells are capable of proliferating and making IFN-gamma plus IL-2, IL-4, IL-5, and IL-10 when stimulated with soluble egg Ag and, therefore, appear Th0-like. After 7 to 10 days, IFN-gamma production is severely depressed but the response continues to be characterized by IL-4, IL-5, IL-10, and IL-2. Depletion studies indicate that CD4 cells are the major population responsible for Ag-mediated proliferation and cytokine production. Results show that schistosome eggs are autonomous inducers of vigorous Th2-like effector responses. Further, our data, from a system that utilizes an in vivo priming step, support the contentions that skewed Th responses develop via an intermediate Th0 stage is accompanied by a loss of the MEL-14 surface marker and an increase in Pgp-1 expression.

Animals↗
PubMed1992

Regulation of germ-line epsilon transcription and induction of epsilon switching in cloned EBV-transformed and malignant human B cell lines by cytokines and CD4+ T cells.

IL-4 induces germ-line epsilon transcript synthesis in normal human B cells, but a second signal provided by CD4+ T cells is required for subsequent production of productive epsilon mRNA and IgE synthesis. In the present study we demonstrate that IL-4 specifically induces germ-line epsilon transcripts in most EBV lymphoblastoid (LCL) and EBV+ and EBV- Burkitt's lymphoma (BL) cells without inducing IgE synthesis. However, cocultivation of cloned sIgM+, sIgE- EBV-LCL or BL cells with activated CD4+ T cell clones in the presence of IL-4 resulted in IgE production in 13 to 24% of the wells. Analysis of rearranged DNA in IgE-producing cloned BL cells indicated that epsilon switching occurred through a recombination deletion event. IgE production is a stable feature of the cloned switched EBV-LCL and BL cells because these cells continued to produce relatively high levels of IgE in the absence of IL-4 and CD4+ T cells. Induction of IgE synthesis was blocked by IFN-gamma, IFN-alpha, and transforming growth factor beta (TGF-beta), but only TGF-beta inhibited IL-4-induced germ-line epsilon mRNA expression. These results suggest that the inhibitory effects of TGF-beta are mediated via inhibition of germ-line epsilon expression, whereas IFN-alpha and IFN-gamma block other steps in the regulatory processes resulting in induction of IgE synthesis by established human B cell line cells. Our results indicate that the same set of signals that induce normal B cells to switch to IgE synthesis also induce high frequency epsilon switching in cloned established EBV transformed and malignant B cell lines including classical cell lines such as JY and BL-2.

B-Lymphocytes↗
PubMed1992

Spectrum of disease in persons with human immunodeficiency virus infection in the United States.

OBJECTIVE: To describe the spectrum of disease in persons with human immunodeficiency virus (HIV) infection. DESIGN: Retrospective survey of medical records. SETTING: More than 50 clinics, hospitals, and private medical practices in nine US cities. PATIENTS: A total of 626 women and 7008 men 13 years of age or older with HIV infection who received medical care from January 1990 through March 1991 were consecutively enrolled. MAIN OUTCOME MEASURES: Any history of diseases in the 1987 case definition for the acquired immunodeficiency syndrome (AIDS), and during the 12-month period preceding enrollment (baseline period), the occurrence of other major diseases, hospitalizations, and results of CD4+ lymphocyte counts. RESULTS: Thirty-two percent of persons met the 1987 case definition for AIDS. The occurrence of an AIDS-indicator disease during the baseline period ranged from 3% (33/1011) to 46% (1254/2748) among persons with CD4+ lymphocyte counts of 0.50 x 10(9)/L or greater and fewer than 0.20 x 10(9)/L (greater than or equal to 500 and less than 200 CD4+ lymphocytes per microliter), respectively, and, at comparable CD4+ lymphocyte levels, was similar among women compared with men, and among persons who reported intravenous drug use compared with men who reported male-to-male sex. The frequency of one or more other major infectious diseases (eg, other pneumonias, bacterial sepsis, pulmonary tuberculosis) ranged from 6% to 16% among persons with CD4+ lymphocyte counts of 0.50 x 10(9)/L or greater and fewer than 0.20 x 10(9)/L, respectively; these illnesses were also associated with a history of intravenous drug use. Among persons who did not meet the 1987 AIDS case definition, 30% of those with an available CD4+ lymphocyte count had fewer CD4+ cells than 0.20 x 10(9)/L, 8% had one or more major infectious diseases, and 14% had one or more hospital admissions. CONCLUSIONS: For every person with AIDS at these sites, two additional persons with HIV infection were receiving medical care, many of whom had severe immunosuppression and a broad spectrum of serious HIV-related disease.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Comparison by race of total serum IgG, IgA, and IgM with CD4+ T-cell counts in North American persons infected with the human immunodeficiency virus type 1.

European patients with human immunodeficiency virus type 1 (HIV-1) infection have been reported to have lower titers of anti-p24 antibody than Central African HIV seropositive patients. Recently, black HIV positive patients in the United States were reported to be more likely to have detectable anti-p24 antibodies, less p24 antigenemia, and higher combined serum immunoglobulins than white HIV positive patients. We measured individual total serum immunoglobulins in 853 HIV positive patients (94% male; 58% white and 42% black) on their initial medical evaluation and compared them with CD4+ T-cell counts. Blacks had notably higher IgG levels (p = 0.001) across the entire spectrum of CD4+ T-cell counts. Serum IgM levels were slightly higher in blacks. IgA levels were not significantly different between the races, although the trend (p = 0.006) was toward higher levels in whites. We also measured these three serum immunoglobulins in 60 HIV seronegative, healthy blood donors (30 black and 30 white). In this control group, blacks had statistically higher IgG and IgA levels than whites. A review of the literature prior to the HIV/acquired immune deficiency syndrome epidemic also supports the view that racial differences in IgG levels are not specific for HIV infection. We speculate that racial differences in humoral immunity, independent of geography or strain of HIV, may account for differences in anti-HIV antibody levels and HIV antigenemia.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Outpatient management of patients infected with human immunodeficiency virus.

The outpatient management of patients infected with human immunodeficiency syndrome is reviewed. Patients with CD4+ cell counts of greater than 0.5 x 10(9)/L (500/mm3) require no specific intervention except vaccination against influenza, pneumococcus, and possibly hepatitis B. They should have a follow-up examination every 3 to 6 months. Because of its success in preventing the progression of the disease, zidovudine (AZT), 100 mg five times per day, is recommended for patients with CD4+ cell counts of less than 0.5 x 10(9)/L (500/mm3). During this stage of the disease, a patient should be seen every 1 to 3 months and monitored for drug toxicity and disease progression. Patients with CD4+ counts of less than 0.2 x 10(9)/L (200/mm3) are at high risk of developing Pneumocystis carinii pneumonia. Prophylaxis with oral trimethoprim-sulfamethoxazole (one double-strength tablet three times weekly) or dapsone (100 mg three times weekly) is recommended. Treatment costs for the patient with CD4+ cells less than 0.5 x 10(9)/L (500/mm3) are at least $3000 per year.

Adult↗
PubMed1992

Coexpression of CD4 and CD8 on mitogen-activated peripheral blood T cells from children with asthma: possible involvement of interleukin 4.

Mononuclear cells were isolated from the peripheral blood of 28 asthmatic and 18 healthy children aged 3 to 16 years. The cells were stimulated with phytohemagglutinin for 96 hours. Activated cells were detected microscopically by MTT staining. Expression of cell surface antigens was detected by indirect immune fluorescence using CD4-specific and CD8-specific monoclonal antibodies. Results indicate an enhanced expression of CD8 on mitogen-activated T cells from asthmatic children compared with cells from healthy controls (median 43% versus 27%). Further experiments revealed that CD8 is coexpressed with CD4 on activated lymphocytes. Coexpression is significantly enhanced with lymphocytes from asthmatic patients compared with normal controls. In addition, interleukin 4 is able to enhance this coexpression with lymphocytes from healthy but not asthmatic children suggesting an in vivo preactivation of lymphocytes from asthmatic patients with interleukin 4.

Adolescent↗
PubMed1992

Use of monitored CD4 cell counts: predictions of the AIDS epidemic in Scotland: CD4 Collaborative Group.

OBJECTIVE: We describe the CD4 database of the Scottish Immunology Laboratories, and its uses and limitations for making short-term predictions of a CD4 cell count less than or equal to 200 x 10(6)/l (CD4(200)) and of adult AIDS cases in Scotland. DESIGN: The date of the earlier of two consecutive samples (typically 3 months apart) both with CD4 cell counts less than or equal to 200 x 10(6)/l was taken to define when a patient had passed the CD4(200) threshold (referred to as a CD4(200) case). The CD4 database comprises HIV-1-seropositive adults in the four main risk groups [homosexual/bisexual (1), injecting drug users (IDU; 2), heterosexual contact (3), and undetermined (9)] from Scotland's three principal areas of population (Lothian, Tayside and Strathclyde) who have had a CD4 cell count of less than or equal to 500 x 10(6)/l. SETTING: Three hospitals in Scotland, the Communicable Diseases (Scotland Unit) and the Medical Research Council Biostatistics Unit, Cambridge, UK. PATIENTS, PARTICIPANTS: The CD4 database at 31 December 1990 listed 813 patients (of whom 52% were IDU): 390 were CD4(200)/AIDS cases (of whom 44% were IDU) and 192 were AIDS cases (of whom 32% were IDU). RESULTS: Individuals in risk groups 1, 2 and 3 were nearly equally represented among newly diagnosed HIV-1 infections in 1990. However, among patients with moderate immunodeficiency, IDU accounted for 50% of the total number. Co-incidence of first CD4 cell count with CD4(200) diagnosis was recorded for only 28% of IDU, but in over 50% of cases for each of the other exposure groups (57%). There was a highly significant decrease of around 80 x 10(6)/l per calendar-year-of-referral in first CD4 cell counts for patients on the CD4 database; and decreases of around 40 x 10(6)/lper decade of age at referral. Since 1988, median time from CD4(200) to AIDS diagnosis in Scotland has been approximately 2 years. Back-projection was applied to annual CD4(200)/AIDS diagnoses before 31 December 1990 and to AIDS diagnoses. From AIDS diagnoses, the central epidemic scenario underestimated past HIV-1-antibody-positive reports (up to the end of 1985). More dramatic underestimation was occasioned by back-projection from CD4(200)/AIDS diagnoses [319 inferred HIV infections compared with 445 HIV-1-antibody-positive reports to Communicable Diseases (Scotland) Unit]. CONCLUSIONS: First CD4 cell counts should complement new HIV-1 diagnoses. Past referrals for immunological monitoring were not uniform between risk groups in Scotland. Underascertainment of CD4(200) cases is a problem when CD4(200) cases are used as a basis for back-projection. More information concerning the incubation distribution from HIV seroconversion to CD4(200) diagnosis is required. It is likely that there are twice as many CD4(200)/AIDS as there are diagnosed cases of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Distinct T cell specificities are induced with the authentic versus recombinant Plasmodium berghei circumsporozoite protein.

Plasmodium berghei sporozoite (SPZ)-immune lymph node (LN) cells obtained from mice of different H-2 haplotypes were analyzed for the presence of circumsporozoite (CS) protein-reactive T cells in proliferative assays. Although lymphocytes from each strain responded in vitro to the priming Ag and to the soluble rCS protein, they did not respond to CS protein synthetic peptides. Parallel analysis of rCS protein-primed LN cells revealed that the two Ag are unequal in generating T cell specificities: although SPZ priming did not induce CS protein peptide-reactive T cells, priming with rCS protein did. Not being privy to the processing and presentation of SPZ Ag, we postulated that a different order of processing of the authentic, i.e., SPZ-associated CS protein vs soluble rCS protein might be responsible for the generation of different T cell specificities. Accordingly, authentic CS protein might not be processed by APC, or the processed fragments might obscure the recognition of smaller peptide fragments. Therefore, we subjected the SPZ to three cycles of a freeze/thaw procedure and used the denatured SPZ preparation for priming. We observed that contrary to priming with the authentic SPZ, denatured SPZ generated T cells reactive to some of the CS protein synthetic peptides. The hypothesis that each form of the SPZ Ag is subject to a unique Ag processing was also confirmed in experiments demonstrating a lack of recognition of the authentic CS protein by rCS protein-primed LN cells. Hence, the evidence presented in this work that complex protozoan Ag, such as Plasmodia, might present different requirements for Ag-specific T cell induction/activation not only enhances the basic understanding of the immune system, but is essential for the development of antimalaria vaccine(s). In addition, these observations support the hypothesis that the molecular context of the priming Ag influences the outcome of T cell specificities, by providing evidence that the authentic CS protein induces a T cell repertoire that is distinct from that induced by the rCS protein.

Amino Acid Sequence↗
PubMed1992

Cellular mechanisms of the antitumor activity of recombinant IL-6 in mice.

The systemic administration of human rIL-6 to mice resulted in the regression of established, 3-day pulmonary micrometastases from two weakly immunogenic tumors, but not from a nonimmunogenic tumor, in the absence of observable toxicity. Although IL-6 alone failed to have a significant therapeutic impact on advanced, 10-day pulmonary macrometastases from weakly immunogenic tumors, substantial cure rates of mice could be achieved when this cytokine was combined with cyclophosphamide. Histologic analysis of the lungs of mice receiving IL-6 revealed infiltration with lymphoid cells during the regression of pulmonary nodules from a weakly immunogenic tumor. IL-6-mediated tumor regression could be abrogated after selective in vivo depletion of either CD4 or CD8 T cell subsets by the systemic administration of specific mAb. In vivo generation of tumor-specific CTL, but not of lymphokine-activated killer cells, was detected in the lungs of IL-6-treated mice during regression of pulmonary metastases. Collectively, these findings demonstrate a role for IL-6 in the treatment of established solid tumors that have the capacity to elicit T cell responses in the host. Differences in host cellular mechanisms involved in tumor regression mediated by immunotherapy using IL-6 vs IL-2 are discussed.

Animals↗
PubMed1992

Immune serum markers and CD4 cell counts in HIV-infected intravenous drug users.

We examined the association of three serum immune markers with CD4 cell counts in a large cohort of i.v. drug users with and without human immunodeficiency virus (HIV) infection. Levels of beta 2-microglobulin and neopterin were significantly elevated in HIV-infected subjects and increased in association with decline in CD4 cell counts (all p less than 0.001). Serum IgA levels in HIV-seropositive individuals were significantly elevated only when the CD4 cell count was less than 200/microliters (p less than 0.001). After controlling for HIV status and CD4 count, recent history of hepatitis was associated with significantly higher beta 2-microglobulin (p = 0.028) and marginally higher neopterin (p = 0.052) levels. There was no association of race, gender, or drug use patterns with levels of serum immune markers after controlling for HIV status and CD4 count. These data indicate that immune activation is coupled with immunosuppression in HIV-infected i.v. drug users. In addition, beta 2-microglobulin and neopterin levels are elevated in persons with a recent history of hepatitis but not in those with recent non-AIDS-defining bacterial infections. Markers of immune activation do not vary by race, gender, or drug use patterns among i.v. drug users.

Biomarkers↗
PubMed1992

[HIV-associated malignant lymphomas].

In a retrospective analysis of data from 35 cases with malignant lymphoma from a cohort of 2017 HIV-infected patients, the stage of HIV-disease, the CD4 counts at the time of diagnosis, and the use of antineoplastic agents or radiotherapy were correlated with outcome. 6 patients had Hodgkin's lymphoma (HL) and 29 non-Hodgkin-lymphoma (NHL). 11 of these lymphomas were classified according to the international working formulation (IWF) as high grade (H, I and J, respectively) and 8 as intermediate grade (G). 10 could not be classified. 22 patients with NHL had stage IV disease according to the Ann Arbor classification, all of whom had manifestations at extranodular sites. 23 patients with NHL were treated with multiagent chemotherapy (18 with m-BACOD or CHOP, 5 patients with various other regimens) and four of them had additional radiotherapy. One patient received radiotherapy only. Two of 24 treated patients showed complete and five a partial response. Median survival of patients without treatment (all of them in poor general condition at the time of diagnosis) was 1.8 months and treated patients survived a median of 5 months. The pretreatment CD4 count was the most important predictor of survival. Patients with prior Aids-diagnosis showed a tendency towards shorter survival. The observed remission rate indicates that HL in HIV-infected patients is better treatable than HIV-associated NHL. However, the overall outcome of HL in our patients was clearly less favorable compared to the course of HL usually seen in patients without HIV infection. The proportion of patients with HL among all patients with malignant lymphoma and HIV disease was unexpectedly larger in our cohort compared to others. Therefore, a possible association of HL and HIV infection, as addressed by several other authors, needs further clarification.

Adult↗
PubMed1992

[Expression of low-affinity Fc epsilon receptors on circulating monocytes in patients with inflammatory rheumatic diseases].

In patients with scleroderma, high proportions of circulating CD23+ monocytes could be detected by FACS analysis as compared with controls. Supernatants obtained from lymphocytes yielded high amounts of interleukin-4-(IL-4-)like activity. The results suggest that IL-4 contributes to monocyte activation in scleroderma. There were no correlations with serum IgE, or numbers of naive and memory-CD4+ lymphocytes.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1992

Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus.

In 1989, the United States Public Health Service convened a Task Force of experts to consider the expanding knowledge base about prevention of Pneumocystis carinii pneumonia (PCP) among adults and adolescents (greater than or equal to 13 years of age) with human immunodeficiency virus (HIV) infection. This Task Force concluded that the morbidity, mortality, and cost due to PCP could be substantially reduced by appropriate use of antipneumocystis prophylaxis in subgroups of HIV-infected patients known to be at high risk, and developed recommendations for the administration of prophylactic regimens (1). The recommendations state that CD4+ T-lymphocyte counts should be monitored prospectively at 3- to 6-month intervals and prophylaxis should be instituted when patients become immunologically susceptible to PCP. Susceptibility was defined by a CD4+ T-lymphocyte count less than 200 cells/microliters or less than 20% of total circulating lymphocytes, or the occurrence of a previous episode of PCP. The goal of this approach was to reduce the frequency both of initial episodes of PCP (primary prophylaxis) and of relapses or recurrences (secondary prophylaxis). Either oral trimethoprim-sulfamethoxazole (TMP-SMX) or aerosol pentamidine was recommended for prophylaxis, but because direct comparative data were lacking, neither regimen was endorsed as "preferred." Since the recommendations were issued in 1989, additional information has become available about the efficacy and safety of aerosol pentamidine and oral TMP-SMX. A trial sponsored by the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group compared these two regimens in a prospective randomized study; in August 1991, this study was terminated by an independent data and safety monitoring board because statistically significantly fewer recurrences of PCP were observed in the oral TMP-SMX group than in the aerosol pentamidine group (2). On the basis of this finding and other studies assessing PCP prophylaxis, the Task Force was reconvened on October 5, 1991. This report contains the revised recommendations issued by the Task Force.

Administration, Oral↗
PubMed1992

[Lymphocytic alveolitis in the early stages of HIV infection: correlation with biological and prognostic factors].

Broncho-alveolar lavage was performed to assess the degree of pulmonary lymphocytic alveolitis in 32 asymptomatic patients who were infected with the Human Immunodeficiency Virus (VIH). The patients were stages II and III of the CDC classification and the aim of the study was to determine the frequency, nature and prognostic role of the findings. 62.5% of the subjects (20/32) presented with a lymphocytic alveolitis which consisted predominantly of CD8 lymphocyte (64.3 +/- 3.5%), in the absence of an opportunistic infection or broncho-pulmonary tumours. Two sub-populations of alveolar CD8 were shown at comparable levels, a) sub-population CD8+D44+ (22.1 +/- 5%), in whom we showed the possession of cytotoxic activity in particular specific for VIH; b) sub-population CD8+CD57+ (19.6 +/- 3%) which we have shown to be capable in vitro of inhibiting the effector phase of cytotoxic activity of CD8+D44+ alveolar cells specific for VIH. In this group of 32 patients the occurrence of an alveolitis was not correlated with the usual prognostic factors of infection by VIH measured simultaneously with broncho-alveolar lavage (the level of CD4+ blood lymphocytes, and the beta 2-plasma microglobulins and the presence of p24 antigenaemia). In addition the level of CD4 lymphocytes supperior to 400/mm3 and of beta 2-microglobulins less then 3 mg/l whether a lymphocytic alveolitis was there or not confirmed the relatively poorly developed state of the VIH infection in these asymptomatic patients. Also the occurrence of a lymphocytic alveolitis did not seem to be linked to progression of the disease in the group of patients studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗