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Biomedical subjects

M C Sneller

Publications and source records attributed to M C Sneller.

At least 19 recordsLinked to original sources
PubMed1997

Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.

Anemia, Hemolytic, Autoimmune↗
PubMed1997

Pathogenesis of vasculitis syndromes.

The pathogenesis of vasculitis is complex and involves a variety of mechanisms acting in concert to bring about necrotizing inflammation of blood vessel walls. In recent years, there has been considerable progress in dissecting the immunologic abnormalities present in specific vasculitis syndromes. The primary immunopathogenic events that initiate the process of vascular inflammation and blood vessel damage, however, are still largely unknown. Although the cause of most vasculitis syndromes remains a mystery, advances in molecular and cellular immunology have defined many of the effector mechanisms that mediate inflammatory vascular damage. In this regard, modulation of the inflammatory response by specific cytokine and adhesion molecule antagonists is now possible and may prove beneficial in the treatment of vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1996

Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis.

OBJECTIVE: To describe the incidence of, clinical manifestations of, and risk factors for cyclophosphamide-induced urinary bladder toxicity in patients treated for nonmalignant disease. DESIGN: Retrospective analysis of patients followed at the National Institutes of Allergy and Infectious Diseases from 1967 to 1993. SETTING: The Warren G. Magnuson Clinical Center of the National Institutes of Health (NIH). PATIENTS: 145 patients who received cyclophosphamide for the treatment of Wegener granulomatosis and were followed for 0.5 to 27 years (median, 8.5 years), for a total of 1333 patient-years. MEASUREMENTS: Clinical characteristics, cystoscopic findings, results of cytologic examination of urine, surgical pathology, and total dose and duration of cyclophosphamide therapy were recorded and analyzed using a computer-based information retrieval system. RESULTS: Nonglomerular hematuria occurred in 73 of 145 patients treated with cyclophosphamide (50%). Sixty of the 73 patients with nonglomerular hematuria (82%) had cystoscopy at the NIH. Forty-two of the 60 patients (70%) who had cystoscopy had macroscopic changes consistent with cyclophosphamide-induced bladder injury. Seven patients (5%) developed transitional-cell carcinoma of the urinary bladder. In 6 of these 7 patients, the total cumulative cyclophosphamide dose exceeded 100 g, and the cumulative duration of cyclophosphamide therapy exceeded 2.7 years. Before they were given a diagnosis of bladder cancer, all 7 patients had had one or more episodes of microscopic or gross nonglomerular hematuria. In contrast, none of the 72 patients who had never had nonglomerular hematuria developed bladder cancer. Cox proportional hazards regression analysis showed that only microscopic nonglomerular hematuria was a significant risk factor for the development of bladder cancer (P < 0.01). CONCLUSION: Long-term oral cyclophosphamide therapy is associated with substantial urotoxicity, including the development of transitional-cell carcinoma of the urinary bladder. In this cohort of patients, the estimated incidence of bladder cancer after the first exposure to cyclophosphamide was 5% at 10 years and 16% at 15 years. Nonglomerular hematuria was a frequent manifestation of cyclophosphamide-induced cystitis, and it identified a subgroup of patients at high risk for the development of bladder cancer.

Aged↗
PubMed1996

Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis.

OBJECTIVE: To determine the clinical features and optimal treatment of subglottic stenosis (SGS) in patients with-Wegener's granulomatosis (WG). METHODS: Review of 43 patients with SGS and treatment of 20 patients with intratracheal dilation-glucocorticoid injection therapy. RESULTS: SGS developed in 43 of 189 patients with WG who were followed up at the National Institutes of Health Clinical Center. The diagnosis of SGS occurred in the absence of other features of active. WG in 21 of 43 patients (49%). In 21 patients (49%), SGS began while the patient was receiving systemic immunosuppressive therapy for disease activity involving other sites. Tracheostomy was required in 10 of 18 patients (56%) who were treated with systemic immunosuppressive therapy. In 20 patients treated with intratracheal therapy, none required tracheostomy and 6 with previous tracheostomies were decannulated. CONCLUSION: SGS often occurs independently of other features of active WG and is frequently unresponsive to systemic immunosuppressive therapy. Intratracheal dilation-injection therapy provides a safe and effective treatment for WG-associated SGS and, in the absence of major organ disease activity, should be used without concomitant systemic immunosuppressive agents.

Adult↗
PubMed1996

Consensus symposium on combined antiviral therapy; overview of interferon and IL-2 combinations for the treatment of HIV infection.

Among the immunomodulatory cytokines that have been evaluated for the treatment of HIV disease, alpha-interferon and interleukin-2 (IL-2) have been the most extensively studied. Monotherapy with alpha-interferon is effective therapy for HIV-associated Kaposi's sarcoma (KS) in patients with CD4 counts > 150 cells/mm3. However, the doses necessary to achieve a significant anti-tumor effect are often poorly tolerated. Combination therapy with alpha-interferon and zidovudine is associated with dose-limiting toxicities and an anti-tumor effect similar to that of higher dose alpha-interferon monotherapy. The combination of alpha-interferon and zidovudine can synergistically inhibit HIV replication in vitro; however, in vivo results suggest the anti-HIV effect of this combination is no greater than that seen with zidovudine monotherapy. Whether combination of interferon-alpha and other antiviral drugs will be useful in the treatment of HIV infection remains to be seen. Recent studies employing intermittent courses of IL-2 combined with continuous antiretroviral therapy indicate that sustained rises in CD4 counts can be achieved. The ability of IL-2 therapy to result in a sustained rise in CD4 counts is critically dependent on the pre-treatment CD4 count. The immunologic and clinical significance of these IL-2-induced increases in CD4 counts is unknown. Larger, controlled trials are currently underway to evaluate the role of intermittent IL-2 therapy in HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Virtual bronchoscopy: segmentation method for real-time display.

Computed tomography (CT) data sets obtained in 14 patients were used in a segmentation method for virtual bronchoscopy (VB). The method constrained the distance of propagation of a region-growing algorithm. The resulting three-dimensional bronchial model was a faithful representation of the source CT data and could be manipulated in real time at frame rates of one to two frames per second. Preliminary data showed that 90% of bronchi (up to third order) measureable on multiplanar CT reformations were also measurable at VB. The bronchial diameters measured at VB were within 1 mm of those measured on multi-planar reconstructions of the CT data.

Adult↗
PubMed1995

An analysis of forty-two Wegener's granulomatosis patients treated with methotrexate and prednisone.

OBJECTIVE: To determine the efficacy of low-dose methotrexate (MTX) plus prednisone in the treatment of Wegener's granulomatosis (WG). METHODS: An open-label study of weekly low-dose MTX plus prednisone for the treatment of WG was performed. Forty-two patients who did not have immediately life-threatening disease were enrolled into the study. Outcome was determined by clinical characteristics and pathologic, laboratory, and radiographic findings. RESULTS: Weekly administration of MTX and prednisone resulted in remission of disease in 30 of the 42 patients (71%). The median time to remission was 4.2 months. The estimated median time to relapse for all patients in whom remission was achieved was 29 months. Eight patients who had relapses were treated with a second course of MTX plus prednisone, and a second remission was induced in 6 of the 8 (75%). CONCLUSION: Weekly low-dose MTX was shown in this study to be an acceptable alternative form of therapy for selected patients with WG who do not have immediately life-threatening disease or who have developed serious cyclophosphamide-associated toxicity.

Administration, Oral↗
PubMed1994

Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate.

OBJECTIVE: To identify the role of methotrexate (MTX) in the treatment of persistent or recurrent Takayasu arteritis that is refractory to treatment with glucocorticoids (GC) alone. METHODS: An open-label pilot study of weekly low-dose MTX+GC treatment was performed. Outcome was evaluated according to clinical characteristics, laboratory abnormalities, findings on routinely performed angiographic studies, and ability to withdraw GC and MTX therapy. Eighteen patients entered the study; 2 dropped out, and 16 were followed up for a mean period of 2.8 years (range 1.3-4.8 years). RESULTS: Weekly administration of MTX (mean stable dose of 17.1 mg) and GC resulted in remissions in 13 of 16 patients (81%). However, 7 patients (44%) had relapses as GC was tapered to or near discontinuation. Retreatment again led to remission, and 3 of 7 patients in this group have successfully stopped GC therapy. Of those patients who achieved remission, 8 (50%) have sustained remissions of 4-34 months (mean 18 months), and 4 of this group have not required GC or MTX therapy for 7-18 months (mean 11.3 months). Three patients experienced disease progression in spite of treatment. CONCLUSION: About half of all Takayasu arteritis patients have chronic active disease for which GC therapy alone does not provide sustained remissions that allow withdrawal of treatment. Weekly low-dose MTX is an effective means of inducing remission and minimizing GC therapy and toxicity in most of these patients. Further long-term studies will be required to assess the durability of remission and the need for maintenance MTX therapy in this subset of Takayasu arteritis patients.

Adolescent↗
PubMed1994

Complications of corticosteroid therapy.

The biochemistry and pharmacology of corticosteroids are reviewed as related to their clinical use, inclusive of head and neck disease. Complications and their management are discussed, as is a dosage regimen considered useful for most patients. Alternate-day corticosteroid therapy is stressed, especially in the long-term management of autoimmune and inflammatory disorders.

Anti-Inflammatory Agents↗
PubMed1994

A unique syndrome of immunodeficiency and autoimmunity associated with absent T cell CD2 expression.

CD2 is a glycoprotein expressed on the surface of human T cells that mediates adhesion between T cells and antigen presenting cells. CD2 also functions in concert with the T cell receptor to transduce signals that lead to T cell activation. The CD8 and CD4 molecules are transmembrane glycoproteins that are expressed on mutually exclusive populations of mature T cells and bind to determinants on major histocompatibility complex class I and class II molecules respectively. Like CD2, CD4 and CD8 function to promote adhesion between T cells and antigen presenting cells and potentiate signaling via the T cell receptor. We studied a patient with idiopathic lymphopenia and disseminated infection with Mycobacterium avium. The patient also suffered from recurrent deep venous thrombosis in association with anticardiolipin and anti-DNA antibodies. Peripheral blood T cells from this patient were polyclonal and expressed no detectable CD2 RNA or protein as determined by northern blotting, immunofluorescent staining with anti-CD2 antibodies, and failure to form rosettes with sheep red blood cells. In addition, the majority (85%) of this patient's T cells did not express either CD4 or CD8 but did express the alpha/beta T cell receptor. T cells from this patient failed to respond to stimulation with alloantigen or specific antigen. In contrast, there was a normal response to stimulation with immobilized anti-CD3 antibody. The clinical and immunologic findings in this patient provide in vivo evidence that the accessory molecules CD2, CD4, and CD8 play important roles in the regulation of normal human T cell activation.

Antigens, Surface↗
PubMed1994

Common variable immunodeficiency: diagnosis and management.

OBJECTIVE: Common variable immunodeficiency is a heterogeneous syndrome characterized by humoral immunodeficiency, recurrent bacterial infections, and a variety of immunologic abnormalities. The goal of this article is to review the pathogenesis, clinical manifestations, diagnosis, and management of common variable immunodeficiency. DATA SOURCES: References are limited to the English language literature. Sources include computerized databases and bibliographies of recent articles and books. STUDY SELECTION: References that made important contributions to our understanding of the pathogenesis, clinical manifestations, diagnosis, and treatment of this disease were selected for inclusion in this review. RESULTS AND CONCLUSION: Common variable immunodeficiency is an idiopathic state of immune dysregulation that results in impaired antibody synthesis and the development of recurrent bacterial infections. This syndrome is also associated with a variety of autoimmune and neoplastic disorders. Effective management of these patients includes intravenous immunoglobulin replacement, vigorous treatment of infections, and readiness to promptly evaluate and treat unusual autoimmune and neoplastic complications should they appear.

Common Variable Immunodeficiency↗
PubMed1993

Functional abnormalities of CD8+ T cells define a unique subset of patients with common variable immunodeficiency.

A substantial subgroup of patients with common variable immunodeficiency (CVI) exhibit an abnormal T-cell phenotype characterized by a low CD4/CD8 ratio associated with a significant increase in the absolute number of CD8+ T cells (CVI4/8low patients). In the present study, we examined the phenotypic and functional properties of purified T-cell subsets in this group of CVI patients. CD8+ T cells from CVI4/8low patients manifested increased expression of HLA-DR and CD57 and decreased expression of CD45RA as compared with CD8+ T cells from normal controls. When stimulated with anti-CD3 and phorbol 12-myristate 13-acetate, purified patient CD8+ T cells exhibited significantly decreased proliferation, c-myc expression, and interleukin-2 (IL-2) production compared with that of normal CD8+ T cells. Nevertheless, mitogen-activated patient CD8+ T cells secreted elevated amounts of gamma-interferon and IL-5 and normal amounts of IL-4. This abnormal pattern of proliferation and cytokine production was limited to the CD8+ T-cell subset as CD4+ T cells from these patients exhibited normal proliferation and cytokine production. In further functional studies, purified CD8+ T cells from CVI4/8low patients manifested increased cytotoxic T-lymphocyte activity and suppressor activity, as compared with normal CD8+ T cells, when they were tested in (1) an anti-CD3 "redirected" cytotoxicity assay and (2) a suppressor assay consisting of CD8+ T cells and Staphylococcus aureus Cowan I (SAC) plus IL-2-stimulated normal (allogeneic) B cells. In the latter case, patient CD8+ T cells suppressed IgG production, but not IgM production. Finally, in studies to evaluate the role of patient CD8+ T cells in the pathogenesis of hypogammaglobulinemia, we determined the capacity of SAC and IL-2 to induce Ig production in highly purified patient B cells, ie, in the absence of patient CD8+ T cells. We found that, whereas B cells from one patient produced normal amounts of IgG, B cells from three patients were unable to produce normal amounts of IgG under these conditions. These data establish the phenotypic and functional characteristics of CD8+ T cells in CVI4/8low and clearly distinguish CVI4/8low patients from other patients with this syndrome. The data do not support the contention that hypogammaglobulinemia in CVI4/8low patients is due to a direct effect of CD8+ T cells on terminal B-cell differentiation, except in the occasional patient. The abnormal CD8+ T cells may, nevertheless, have more subtle effects of lymphoid function that play a role in disease pathogenesis.

Antibody Formation↗
PubMed1993

NIH conference. New insights into common variable immunodeficiency.

Common variable immunodeficiency (CVI) is a heterogenous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and various immunologic abnormalities. In addition to recurrent infections, patients with this syndrome also have an increased incidence of autoimmune disease and malignancy. Because the spectrum of associated diseases is broad, patients with CVI are seen by various medical specialists. This review discusses the pathogenesis, clinical manifestations, diagnosis, and treatment of CVI.

B-Lymphocytes↗