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Biomedical subjects

R Hirsch

Publications and source records attributed to R Hirsch.

At least 109 records · Page 6Linked to original sources
PubMed1994

Reduction of mortality and lymphadenopathy in MRL-lpr/lpr mice treated with nonmitogenic anti-CD3 monoclonal antibody.

OBJECTIVE: To evaluate the therapeutic efficacy of nonmitogenic anti-CD3 monoclonal antibody (MAb) in a preexisting autoaggressive response, using the MRL-lpr/lpr (MRL/l) murine model of autoimmune disease. METHODS: Female MRL/l mice, 8-10 weeks of age, were treated with nonmitogenic anti-CD3 MAb or phosphate buffered saline and effects on mortality, lymphadenopathy, T cell phenotypes, anti-DNA titers, and total IgG titers were measured. RESULTS: Nonmitogenic anti-CD3 MAb treatment resulted in a dramatic reduction in lymphadenopathy and mortality, as well as an early reduction in alpha/beta+, CD4-, CD8-, Thy+, B220+ (double-negative) lymph node cells. No significant effects on anti-DNA or IgG titers were observed. No morbidity was observed following administration of nonmitogenic anti-CD3 MAb. CONCLUSION: A short course of treatment with nonmitogenic anti-CD3 MAb can suppress preexisting autoimmune responses without inducing the cytokine-mediated toxicity characteristic of mitogenic forms of anti-CD3 MAb. The use of nonmitogenic anti-CD3 MAb may be efficacious in the clinical setting for the treatment of T cell-mediated autoimmune disorders.

Animals↗
PubMed1994

Psychiatric manifestations of systemic lupus erythematosus: clinical features, symptoms, and signs of central nervous system activity in 43 patients.

Forty-three female inpatients with active systemic lupus erythematosus (SLE) were studied by a multidisciplinary team to answer the following research questions: 1) What are the features of the psychopathology in patients with active SLE? and 2) In these patients, what is the relationship between psychiatric disorders and symptoms and signs suggesting activity of SLE in the CNS? Our a priori hypothesis was that, in patients with active SLE, those with psychiatric manifestations would have more symptoms and signs of CNS activity than those without psychiatric manifestations. Psychiatric evaluation consisted of standardized psychiatric instruments and diagnostic criteria. The assessment of SLE systemic and central nervous system (CNS) activity consisted of rheumatologic, neurologic, and ophthalmologic evaluations; serum and cerebral spinal fluid (CSF) analysis; brain computerized tomography (CT); and electroencephalogram (EEG). Twenty-seven patients (63%) presented psychiatric symptoms (Psychiatric Group), and 16 (37%) patients presented no current psychiatric diagnosis (Nonpsychiatric Group). These groups were compared in terms of the above variables. Depressive syndrome was the most frequent diagnosis (44%) followed by delirium (7%) and dementia (5%). Psychiatric symptoms were associated with subjective cognitive impairment (85%) and neurologic abnormality (85%). Widened cortical sulci was the most frequent CT alteration and was equally common in both groups. No statistical difference was found between the 2 groups regarding their general clinical evaluation, serum and CSF exams, or EEG alterations. To determine whether the severity of psychiatric symptoms was related to CNS activity, we divided the 27 patients with psychiatric manifestations into 2 groups: the Major Group--18 patients with major psychopathology, and the Minor Group--9 patients with mild depressive syndromes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Venoatrial pathways after the Mustard operation for transposition of the great arteries: anatomic and functional MR imaging.

PURPOSE: To evaluate spin-echo (SE) and cine gradient-echo (GRE) magnetic resonance (MR) imaging with velocity mapping for detecting late complications of the Mustard operation. MATERIALS AND METHODS: Twenty-one patients were studied with MR imaging 1-22 years after undergoing the Mustard operation. Twenty were also studied with transthoracic echocardiography, 18 with angiocardiography, and five with transesophageal echocardiography. RESULTS: MR imaging showed no venoatrial obstruction in nine patients. This result was confirmed with angiocardiography in seven cases and postmortem examination in one case. In one case, MR imaging demonstrated a leak at the baffle suture line. Of 12 cases with venoatrial obstruction at MR imaging, nine were confirmed with angiocardiography or surgery. There were two false-positive MR studies and one case in which no conclusion was reached. CONCLUSION: With addition of cine GRE sequences and velocity mapping to SE sequences, MR imaging is a useful noninvasive method of investigating late complications of the Mustard operation.

Adult↗
PubMed1994

Diagnosis in adolescents and adults with congenital heart disease. Prospective assessment of individual and combined roles of magnetic resonance imaging and transesophageal echocardiography.

BACKGROUND: The inability to obtain complete diagnoses with transthoracic echocardiography in many adults with congenital heart disease provided the incentive to evaluate prospectively the individual and combined roles of magnetic resonance imaging (MRI) and transesophageal echocardiography (TEE) as "second-line" techniques for unresolved diagnostic problems. METHODS AND RESULTS: Eighty-five patients were studied; 81 had MRI with a 0.5-T magnet to obtain spin-echo images, cine-MRI, and flow-velocity maps. Seventy-nine patients had TEE (37 biplane). A simple score (range, 0 to 1) was used for quantification of the results of MRI and TEE alone, for their comparison (in the 75 patients who had both), and for assessment of their combination. MRI, TEE, or their combination achieved a score of at least 0.75 in 18 of 25 diagnostic categories. A summary of the scores showed that for intracardiac anatomy. MRI scored 0.34, TEE scored 0.71 (P < .0001), and MRI plus TEE scored 0.84 (P < .003); for extracardiac anatomy, MRI scored 0.76, TEE scored 0.23 (P < .0001), and MRI plus TEE scored 0.84 (P = NS); and for hemodynamics and function, MRI scored 0.58, TEE scored 0.41 (P < .05), and MRI plus TEE scored 0.67 (P = NS). Total scores were MRI, 0.52; TEE, 0.50 (P = NS); and MRI plus TEE, 0.80 (P < .0001). MRI and TEE were inadequate for collateral and coronary arteries and pulmonary vascular resistance. Cine-MRI and flow-velocity maps comprised 43% of the MRI scores. Biplane TEE was better than single plane (scores of 0.59 versus 0.42, P < .0001). CONCLUSIONS: MRI and TEE are important and complementary "second-line" investigations for congenital heart disease. Analysis of their performance in a wide range of diagnostic categories provides guidelines for their judicious application. Where both are available, diagnostic catheterizations are either obviated or simplified.

Adolescent↗
PubMed1993

Effect of allogeneic tumor cells, interleukin-2 and interleukin-6, on the growth of subcutaneous syngeneic tumors.

In the present study we demonstrate the ability of allogeneic M3 tumor cells to induce an antitumor response against the syngeneic tumor, when injected locally together with syngeneic B16 melanoma cells. The replacement of the allogeneic tumor cells with either syngeneic or allogeneic splenocytes had no effect on the growth of the syngeneic tumor. Systemic administration of both interleukin-2 (IL-2) and IL-6 did not affect the antitumor response induced by allogeneic tumor cells. When mice, previously injected with B16 and M3 cells, were rechallenged subcutaneously with B16 tumor cells at a different anatomical site, an inhibitory effect in some, but not all, experiments was observed. Systemic injections of either IL-2 or IL-6 did not alter the antitumor effects of the allogeneic and syngeneic tumor-cell mixtures. The significance of our results in developing immunotherapy modalities based on active immunization with allogeneic tumor cells and selected cytokines is discussed.

Animals↗
PubMed1992

Effects of anti-CD3 monoclonal antibody on engraftment of T-cell-depleted bone marrow allografts in mice: host T-cell suppression, growth factors, and space.

To investigate the role of CD3-positive T cells in allogeneic marrow rejection in mice and to examine the effects of anti-CD3 monoclonal antibody (MoAb) on allogeneic marrow engraftment, a hamster MoAb, 145-2C11, with specificity for the CD3 epsilon portion of the murine T-cell receptor complex was administered to B6 (H-2b) mice that had been sublethally irradiated with 626 cGy and injected with 10 x 10(6) T-cell-depleted B6C3F1 (H-2b/k) bone marrow cells. Lymphoid chimerism status was assessed by flow cytometric analysis of peripheral blood lymphocytes using H-2k-specific MoAb 5 to 6 weeks after bone marrow transplantation. When hosts were treated with 400 micrograms of anti-CD3 MoAb at the time of marrow injection, the percentage of donor-type cells was 75.2% +/- 15.0%, while it was 1.9% +/- 1.2% in untreated mice. It was demonstrated that anti-CD3 MoAb not only suppressed T-cell function but also induced colony-stimulating factors in host mice, and that enhancement of marrow engraftment in anti-CD3 MoAb-treated mice was associated with factor release as well as suppression of host T-cell function. Results were consistent with engraftment being enhanced by a differential response of donor (rather than host) marrow to serum factors in association with host T-cell immunocompromise.

Animals↗
PubMed1992

In the eye of the beholder: pretesting the effectiveness of health education materials.

Health educators at the University of Massachusetts evaluated five posters to determine whether students comprehended, identified with, and were motivated by the messages, which dealt with aspects of safer sex, alcohol use, and stress management. Pretesting, they suggest, provides an opportunity for remedying design flaws before distributing materials, improving effectiveness, and saving money by assuring that the target audience receives the intended message. Six suggestions for improving effectiveness and acceptability of printed health education materials are offered.

Attitude to Health↗
PubMed1992

Prevention of autoimmune diabetes with nonactivating anti-CD3 monoclonal antibody.

Autoreactive T cells mediate diabetes in animal models of insulin-dependent diabetes mellitus (IDDM) and are believed to cause the disease in humans. Therefore, immunotherapies directed against T cells are of particular interest for the treatment of IDDM. One candidate for such immunotherapy is anti-CD3 monoclonal antibodies (MoAbs), but clinical side effects are common with anti-CD3 treatment due to the ability of these MoAbs to activate T cells in vivo. However, F(ab')2 fragments of anti-CD3 are nonactivating and immunosuppressive. We evaluated the effects of whole anti-CD3 MoAb and F(ab')2 fragments in the setting of experimental autoimmune diabetes. Treatment with whole MoAb or F(ab')2 fragments significantly reduced the hyperglycemia induced with multiple low dosages of streptozocin (MDSDM; 232 +/- 23 mg/dl, P less than 0.01 and 235 +/- 16 mg/dl, P less than 0.01 vs. 325 +/- 25 mg/dl, respectively) in male CD1 mice. Both whole MoAb and F(ab')2 fragments suppressed the development of insulitis (P less than 0.001). Treatment with whole MoAb resulted in marked weight loss (10.4 +/- 1.5% of total body wt), and the mice appeared ill and listless, whereas, mice treated with F(ab')2 fragments gained weight (4.9 +/- 5.5% of total body wt) and appeared healthy. Treatment with whole MoAb caused activation of T cells in vivo as reflected by proliferation of freshly isolated spleen cells to recombinant interleukin-2. Depletion of T cells with whole MoAb was more pronounced than with F(ab')2 fragments, and T-cell receptor (TCR) reexpression on remaining cells occurred with F(ab')2 fragments within 48 h after F(ab')2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The T cell receptor in autoimmune diseases.

Autoimmunity is likely the cause of a variety of diseases including systemic lupus erythematosus, rheumatoid arthritis and diabetes. Normally, the body's immune system serves as a defense against a variety of conditions, including, injury, infection and neoplasm. However, for reasons that are currently unclear, the normal regulation of the immune system can breakdown resulting in autoaggressive responses. T cells, especially CD4+ cells, appear to play a predominant role in most autoimmune diseases. We summarize our workshop which focussed on the role of the T cells in autoimmune diseases. We summarize our workshop which focussed on the role of the T cells in autoimmune diseases; the T cell receptor in autoantigen recognition (emphasizing the role of selective T cell receptor V regions in the autoimmune response); and a discussion of possible therapeutic interventions.

Animals↗
PubMed1991

Immunopotentiation of anti-viral and anti-tumor immune responses using anti-T cell receptor antibodies and mitogens.

Although the immunosuppressive properties of anti-CD3 mAbs are now widely recognized, we have accumulated data characterizing the T cell activating properties of these antibodies. While in some situations these activating properties may be viewed as unwanted side-effects (for instance OKT3-mediated T cell activation may be responsible for some of the first dose toxicity seen with patients receiving OKT3 for suppression of allograft rejection), we have shown that anti-CD3 mAb therapy can augment host immune responses and provide protection against some tumors and viral infections. Importantly, this augmented response allows the development of long term, specific immunity. Because the immunosuppressive and activating properties of anti-CD3 mAbs are so closely overlapping, we have sought to identify other agents that are capable of activating T cell subsets selectively. We have found that SEB activates T cell subsets selectively in vivo and that this activation can be exploited to prevent the outgrowth of a malignant murine tumor. Studies currently in progress, including phenotypic and functional analysis of TILs and in vivo T cell subset depletions, should result in a more precise understanding of how SEB-induced T cell activation inhibits tumor growth.

Animals↗
PubMed1991

Differential T cell hyporesponsiveness induced by in vivo administration of intact or F(ab')2 fragments of anti-CD3 monoclonal antibody. F(ab')2 fragments induce a selective T helper dysfunction.

Induction of peripheral T cell anergy associated with stimulation through the TCR complex in vivo has been described in mice using chemically modified APC, staphylococcal enterotoxin B, and intact anti-CD3 mAb. In the latter two models, T cell proliferation, IL-2R expression, and lymphokine production have been demonstrated before subsequent induction of hyporesponsiveness, whereas in the former model, these events have not been observed. To further investigate the relationship between mitogenicity and induction of peripheral hyporesponsiveness, mice were treated with either mitogenic intact anti-CD3 mAb or nonmitogenic F(ab')2 fragments of anti-CD3 mAb. T cells from F(ab')2-treated mice demonstrated a selective decrease in helper functions, with minimal effect on CTL function. Specifically, a marked reduction in ability of Th cells to secrete IL-2 when challenged in vitro with mitogen or alloantigen was observed, which persisted for at least 2 mo after mAb administration and which was independent of T cell depletion. Proliferative function was decreased in CD4+ T cells and could not be fully restored with addition of exogenous IL-2. A helper defect was also evident in vivo, in that F(ab')2-treated mice were deficient in their ability to reject MHC-disparate skin grafts, and in vivo administration of IL-2 reconstituted their ability to reject skin grafts normally. In contrast, T cells from mice treated with intact mAb demonstrated a significant decrease in both CTL and helper functions. A long term reduction in TCR expression on CD4+ cells from F(ab')2-treated mice, and on both CD4+ and CD8+ cells from intact mAb-treated mice was observed. These findings demonstrate that peripheral T cell hyporesponsiveness can be induced in vivo by binding an identical epitope on the TCR complex in the presence or absence of initial proliferation, lymphokine secretion, or IL-2R expression, and that binding to the same epitope can result in varying long term effects on T cell function.

Animals↗
PubMed1991

In vivo administration of anti-CD3 monoclonal antibodies or immunotoxins in murine recipients of allogeneic T cell-depleted marrow for the promotion of engraftment.

The role of host anti-donor cells in rejection of fully allogeneic donor T cell-depleted marrow was investigated by using mAb or immunotoxins directed against T cell or NK cell determinants. Immunotoxins consisting of mAb conjugated to a low oligosaccharide-containing fraction of purified ricin toxin A chain (RTA) facilitated in vivo-depletion of target cell populations. BALB/c and DBA/1 donors were selected based upon their expression (BALB/c) or lack of (DBA/1) hemopoietic histocompatibility (Hh1) Ag, which may serve as targets for donor rejection in C57BL/6 hosts. When studies directed toward eliminating CD3+ cells were performed in both systems, injections of intact anti-CD3 mAb or anti-CD3-RTA reproducibly produced the highest engraftment values. The fact that engraftment values obtained with anti-CD3 or anti-CD3-RTA therapy in allogeneic systems were substantially higher than in syngeneic controls suggested that engraftment stimulatory proteins were released upon TCR engagement. Elevated levels of cytokines and a high mortality rate in allogeneic recipients confirmed that this was the case. Nonstimulatory preparations of anti-CD3F(ab')2 fragments and anti-CD3F(ab')2-RTA promoted engraftment of both types of allogeneic marrow, as measured by short term 125I-IUdR assays, suggesting that stimulation was not a prerequisite for engraftment. Recipients of anti-CD3F(ab')2 or anti-CD3F(ab')2-RTA showed a marked reduction of host CD3+ cells as measured by immunofluorescence and flow cytometry. In long term chimerism studies, recipients of Hh1-disparate marrow and anti-CD3F(ab')2 had a dramatic increase in donor cell engraftment as compared to controls, indicating that positive effects on engraftment were long lived. Studies further showed that BALB/c donor cells exhibiting an Hh1 disparity were rejected by host cells expressing NK1.1 or Ly-1 (NK cells and T cells). In contrast, DBA/1 donor cells that were not Hh1-disparate were rejected by cells expressing Ly-1, but not NK1.1 (T cells only). These studies provide definitive data that CD3+ cells participate in the rejection of either Hh1+ or Hh1null T cell-depleted allografts and offer new strategies for alloengraftment using regimens containing nonmitogenic anti-CD3.

Animals↗
PubMed1991

An analysis of emergency department use by patients with minor illness.

STUDY OBJECTIVE: To describe the motivation for emergency department use by patients with minor illnesses and compare the demographics and social class characteristics of these patients with those of the general ED population. DESIGN: Observational, case-control study. SETTING: Urban ED. TYPE OF PARTICIPANTS: A sample group of 325 adult, nongeriatric patients with minor illnesses was selected by screening all patients registering in the ED between 9:00 AM and 6:00 PM on 15 randomly selected weekdays. A patient was included in this study group if the chief complaint, method of arrival, and subsequent evaluation met predetermined criteria for minor illness. A comparison group (control) was composed of all ED patients (224) who presented during two randomly selected 24-hour periods that did not overlap with the times of study group enrollment. INTERVENTIONS: Sample group patients were interviewed concerning their socioeconomic backgrounds, reasons for using the ED, and perceptions of the urgency of their conditions. Comparison group patients' interviews were confined to the collection of demographic and socioeconomic information. MEASUREMENTS AND MAIN RESULTS: There were more men (P = .12), more self-pay patients (P = .017), and fewer Medicare patients (P less than .001) in the study group. There also was a strong trend toward higher income (P = .059) in the study group. The racial, marital, employment, and educational backgrounds of the two groups were similar. Eighty-two percent of the study group had no chronic illness, and only 36% reported a problem of more than three days' duration. Patients chose to use the ED because of its convenience (23.7%), the absence of previous provider relationships (22.1%), and the inability to make a prompt appointment with their regular provider (19.0%). Major differences existed between the reasons for which different demographic and socioeconomic groups chose ED care. Study group patients believed that less than 24 hours should elapse between the onset of their problem and the time at which they receive medical care. CONCLUSION: There are no major differences in ED use for minor illness patients from different racial, educational, and economic backgrounds. These patients tend to have a low frequency of chronic illness and often have no established health care provider. They choose the ED for its ease of access and the wide scope of care that can be delivered.

Adult↗
PubMed1990

Anti-CD3 F(ab')2 fragments are immunosuppressive in vivo without evoking either the strong humoral response or morbidity associated with whole mAb.

The use of anti-CD3 monoclonal antibodies to treat organ allograft rejection has been complicated by (1) the morbidity associated with the initial dose, (2) the humoral response of the patients against the mAbs, and (3) the generalized immunosuppression induced by the mAbs. We investigated the potential of F(ab')2 fragments of the anti-murine-CD3 mAb, 145-2C11, to avoid these complications in the murine model. Both whole mAb and F(ab')2 fragments induced T cell depletion. However, injection of F(ab')2 fragments of anti-CD3 mAb did not cause T cell activation, and did not induce the morbidity and mortality observed following injection of whole mAb. The humoral response against the F(ab')2 fragments was significantly reduced compared with the response against the whole mAb. Furthermore, repeated administration of F(ab')2 fragments of anti-CD3 mAb resulted in prolongation of allogeneic skin graft survival superior to that seen following treatment with a single dose of whole mAb. Finally, while T cells from mice treated with whole mAb displayed profound suppression of in vitro CTL generation, T cells from mice treated with F(ab')2 fragments had significant in vitro CTL function. These results suggest that the use of F(ab')2 fragments of anti-CD3 mAb may offer significant advantages over whole mAb for the induction and maintenance of immunosuppression.

Animals↗
PubMed1990

Augmentation of tumor cell immunogenicity by viruses--an approach to specific immunotherapy of cancer.

Several viruses have been evaluated as potential agents for cancer treatment using either their oncolytic properties, in order to lyse cancer cells, or their potential augmenting effects on the immune response to tumors. However, the direct oncolytic effect was found to be limited in time, in scope and in specificity, whereas the use of viral oncolysates to augment antitumor immunity was shown to be better than tumor cell homogenates or extracts but inferior to noninfected intact tumor cells, attesting for the importance of membrane architecture in preserving immunogenicity of tumor specific surface antigens. In order to get the maximum benefit from this approach we selected a nonlytic virus-tumor cell combination, using Newcastle disease virus as a nonpathogenic virus, to treat the experimental tumor model, Lewis lung carcinoma (3LL) in mice. The virus effectively infected 3LL cells without any cytopathic effect. The infected cells induced strong antitumor immunity, as judged by the appearance of immune cells in the spleen (Winn test and lymphocytotoxicity) and by the resistance to challenge with the 3LL cells after immunization. The antitumor immunity was superior to that obtained with intact noninfected tumor cells. We also designed a treatment protocol using the same virus-tumor cell preparation to treat mice after tumor inoculation. This treatment resulted in cure of 40% of the animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗