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Howard M Lederman

Publications and source records attributed to Howard M Lederman.

11 recordsLinked to original sources
PubMed2006

Standardization and performance evaluation of mononuclear cell cytokine secretion assays in a multicenter study.

BACKGROUND: Cryopreservation of peripheral blood mononuclear cells has been used to preserve and standardize immunologic measurements for multicenter studies, however, effects of cryopreservation on cytokine responses are incompletely understood. In designing immunologic studies for a new multicenter birth cohort study of childhood asthma, we performed a series of experiments to determine the effects of two different methods of cryopreservation on the cytokine responses of cord and peripheral blood mononuclear cells. RESULTS: Paired samples of PBMC were processed freshly, or after cryopreservation in a Nalgene container (NC) or a controlled-rate freezer (CRF). Although there were some differences between the methods, cryopreservation inhibited PHA-induced IL-10 secretion and Der f 1-induced IL-2 secretion, and augmented PHA-induced IL-2 secretion and spontaneous secretion of TNF-alpha. In separate experiments, NC cryopreservation inhibited secretion of several cytokines (IL-13, IL-10, IFN-gamma, TNF-alpha) by PHA-stimulated cord blood mononuclear cells. With the exception of PHA-induced IL-13, results from fresh and cryopreserved cord blood samples were not significantly correlated. Finally, in reproducibility studies involving processing of identical cell samples in up to 4 separate laboratories, variances in cytokine responses of fresh cells stimulated at separate sites did not exceed those in cryopreserved cells stimulated at a central site. CONCLUSION: Collectively, these studies indicate that cryopreservation can affect mononuclear cell cytokine response profiles, and that IL-10 secretion and antigen-induced responses may be especially vulnerable. These studies also demonstrate that mononuclear cell responses can be standardized for performance in a small number of laboratories for multicenter studies, and underscore the importance of measuring reproducibility and of testing whether cryopreservation techniques alter specific immunologic outcomes.

Algorithms↗
PubMed2006

X-linked agammaglobulinemia: report on a United States registry of 201 patients.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton tyrosine kinase (BTK) that result in the deficient development of B lymphocytes and hypogammaglobulinemia. Because the disorder is uncommon, no single institution has had sufficient numbers of patients to develop a comprehensive clinical picture of the disorder. Accordingly, a national registry of United States residents with XLA was established in 1999 to provide an updated clinical view of the disorder in a large cohort of patients. A total of 201 patients were registered by 66 physicians. The estimated birth rate for the 10-year period of 1988-1997 was 1/379,000. Infection was the most common initial clinical presentation (85%), followed by a positive family history (41%) and neutropenia (11%). Although the average age of diagnosis was younger in patients with a positive family history (mean, 2.59 yr) than in patients with a negative family history (mean, 5.37 yr) (p < 0.001), only 34.5% of patients with a positive family history at the time of their birth were diagnosed before clinical symptoms developed-that is, based on family history alone. Seventy percent of patients had at least 1 episode of otitis, 62% at least 1 episode of pneumonia, 60% at least 1 episode of sinusitis, 23% at least 1 episode of chronic/recurrent diarrhea, 21% at least 1 episode of conjunctivitis, 18% at least 1 episode of pyoderma and/or cellulitis, 11% at least 1 episode of meningitis/encephalitis, 10% at least 1 episode of sepsis, 8% at least 1 episode of septic arthritis, 6% at least 1 episode of hepatitis, and 3% at least 1 episode of osteomyelitis. Fourteen of 201 (6.9%) patients were dead at the time they were entered in the Registry. However, in a prospective 4 /4-year follow-up of living patients, only 3/80 (3.75%) patients died. Causes of death included disseminated enterovirus infection (n = 6), pulmonary insufficiency (n = 5), adenovirus infection (n = 1), sepsis (n = 1), acquired immunodeficiency disease syndrome (AIDS) (n = 1), myocarditis (n = 1), hepatitis (n = 2), and stem cell transplantation (n = 1).

Adolescent↗
PubMed2004

Long-term follow-up of HIV-infected individuals who have significant increases in CD4+ cell counts during antiretroviral therapy.

BACKGROUND: Descriptions of the durability and consequences of immune reconstitution in patients who start highly active antiretroviral therapy (HAART) while severely immunosuppressed are limited. METHODS: Patients with previous CD4+ cell counts <50 cells/mm3, all of whom had HAART-induced increases in CD4+ cell counts of >100 cells/mm3 on 2 separate occasions (measured sequentially at least 4 weeks apart), were enrolled in a prospective trial and observed every 16-32 weeks. Evaluations included assessments for new opportunistic complications, virologic (human immunodeficiency virus [HIV] RNA load) and immunologic (CD4+ cell count) responses, or death. RESULTS: The median follow-up duration for 612 subjects was 184 weeks (range, 8-216 weeks). The rate of increase in CD4+ cell counts was approximately 5.9 cells/mm3 every 8 weeks, with the degree of increase associated with the baseline HIV RNA load (<500 vs. > or =500 copies/mL). Subsequent measurements of virologic suppression based on HIV RNA levels were also associated with predicted CD4+ cell responses. Thirty-three AIDS-defining illnesses were reported (1.75 events per 100 person-years of follow-up); >40% (14 cases) occurred with higher than expected CD4+ cell counts. CONCLUSIONS: CD4+ cell count increases are related to virological control, with continuing increases seen in individuals who are immunosuppressed. Opportunistic illnesses and/or complications are infrequent but can occur at any time, even in patients who maintained an elevated CD4+ cell count.

Adult↗
PubMed2004

Immunodeficiency and infections in ataxia-telangiectasia.

OBJECTIVE: To characterize the immunodeficiency in ataxia-telangiectasia (A-T) and to determine whether the immunodeficiency is progressive and associated with increased susceptibility to infections. STUDY DESIGN: Records of 100 consecutive patients with A-T from the Johns Hopkins Ataxia-Telangiectasia Clinical Center (ATCC) were reviewed. RESULTS: Immunoglobulin (Ig) deficiencies are common, affecting IgG4 in 65% of patients, IgA in 63%, IgG2 in 48%, IgE in 23%, and IgG in 18%. Lymphopenia affected 71% of patients, with reduced B-lymphocyte number in 75%, CD4 T lymphocytes in 69%, and CD8 T lymphocytes in 51%. There was no trend for increased frequency or severity of immune abnormalities with age. Recurrent upper and lower respiratory tract infections were frequent: otitis media in 46% of patients, sinusitis in 27%, bronchitis in 19%, and pneumonia in 15%. Sepsis occurred in 5 patients, in 2 patients concurrent with cancer chemotherapy. Warts affected 17% of patients, herpes simplex 8%, molluscum contagiosum 5%, candidal esophagitis 3%, and herpes zoster 2%. Uncomplicated varicella infection occurred in 44% of patients; 2 patients had more than one clinical episode. No patient had Pneumocystis jerovici pneumonia or a complication of live viral vaccine. CONCLUSIONS: In spite of the high prevalence of laboratory immunologic abnormalities, systemic bacterial, severe viral, and opportunistic infections are uncommon in A-T. Cross-sectional analysis suggests that the immune defect is rarely progressive.

Adolescent↗
PubMed2003

Incomplete immune reconstitution after initiation of highly active antiretroviral therapy in human immunodeficiency virus-infected patients with severe CD4+ cell depletion.

Immune function was observed for 144 weeks in 643 human immunodeficiency virus (HIV)-infected subjects who (1) had nadir CD4+ cell counts of <50 cells/mm3, followed by a sustained increase to > or =100 cells/mm3 after the initiation of HAART, and (2) were enrolled in a randomized trial of continued azithromycin prophylaxis versus withdrawal for prevention of Mycobacterium avium complex disease. The median CD4+ cell count was 226 cells/mm3 at entry and 358 cells/mm3 at week 144. Anergy (80.2% of patients) and lack of lymphoproliferative response to tetanus toxoid (TT; 73%) after immunization and impaired antibody responses after receipt of hepatitis A (54%) and TT (86%) vaccines were considered to be evidence of impaired immune reconstitution. Receipt of azithromycin did not have an effect on CD4+ cell count but was associated with higher rates of delayed-type hypersensitivity responses to TT (25% of subjects who received azithromycin vs. 15% of those who did not; P=.009) and mumps skin test antigen (29% vs. 17%; P=.001). Although the subjects had only partial responses to immune function testing, the rate of opportunistic infections was very low, and none of the tests was predictive of risk.

Acquired Immunodeficiency Syndrome↗
PubMed2003

A study of discontinuing maintenance therapy in human immunodeficiency virus-infected subjects with disseminated Mycobacterium avium complex: AIDS Clinical Trial Group 393 Study Team.

The present nonrandomized prospective study evaluated whether antimycobacterial therapy for disseminated Mycobacterium avium complex (MAC) could be withdrawn from human immunodeficiency virus-infected subjects who experienced immunologic recovery while receiving highly active antiretroviral therapy (HAART). Eligible subjects had received macrolide-based therapy for least 12 months, were asymptomatic for MAC, had received HAART for at least 16 weeks, and had CD4+ T cell counts >100 cells/microL. Forty-eight subjects were enrolled, with a median CD4+ T cell count of 240 cells/microL at the time of discontinuation of MAC therapy. Forty-seven subjects remained MAC free, whereas 1 subject developed localized MAC osteomyelitis. The median duration of follow-up while not receiving therapy was 77 weeks, and the incidence of MAC infection was 1.44/100 person-years (95% confidence interval, 0.04-8.01). Withdrawal of anti-MAC therapy appears to be safe in patients who have been treated with a macrolide-based regimen for at least 1 year and have an immunologic response on HAART.

AIDS-Related Opportunistic Infections↗
PubMed2002

Cryptosporidiosis stimulates an inflammatory intestinal response in malnourished Haitian children.

The mechanisms by which Cryptosporidium parvum cause persistent diarrhea and increased morbidity and mortality are poorly understood. Three groups of Haitian children <18 months old were studied: case patients, children with diarrhea not due to Cryptosporidium, and healthy control subjects. Compared with both control groups, children with acute cryptosporidiosis were more malnourished (including measures of stunting [P=.03] and general malnutrition [P=.01]), vitamin A deficient (P=.04), and less often breast-fed (P=.04). Markers of a proinflammatory immune response, interleukin (IL)-8 and tumor necrosis factor-alpha receptor I, were significantly elevated in the case population (P=.02 and P<.01, respectively), as was fecal lactoferrin (P=.01) and the T helper (Th)-2 cytokine IL-13 (P=.03). The counterregulatory cytokine IL-10 was exclusively elevated in the case population (P<.01). A Th1 cytokine response to infection was not detected. This triple cohort study demonstrates that malnourished children with acute cryptosporidiosis mount inflammatory, Th-2, and counterregulatory intestinal immune responses.

Animals↗
PubMed2002

Ocular manifestations of ataxia-telangiectasia.

PURPOSE: To report the manifestations of ataxia-telangiectasia (A-T) on the ocular sensory and motor systems. DESIGN: A prospective observational case series. METHODS: In a single tertiary care institition, a comprehensive ophthalmologic evaluation was made of patients with A-T as part of a systemic/neurologic evaluation. Sixty-three A-T patients between the ages of 2 and 28 years were examined. RESULTS: In 58 A-T patients whose visual acuity could be measured, best-corrected visual acuity in the better eye was 20/20 to 20/30 in 39 (67%), 20/40 to 20/50 in 17 (29%), and 20/60 to 20/80 in 2 (4%). The mean geometric visual acuity of the better eye was 20/31. Telangiectatic vessels were seen in the bulbar conjunctiva in 57 of 63 patients (91%) and on the skin of the face of 21 patients (33%). Twenty-four of 63 patients (38%) had strabismus. Esodeviations were the most common, seen in 15 individuals. Apraxia of horizontal gaze was observed in 19 of 63 patients (30%). Hypometric saccades were evident in 48 (76%), pursuit abnormalities in 43 (63%), and nystagmus in 18 (29%). Accommodation was deficient in the 54 patients in whom it was measured. No posterior segment vascular anomalies were detected. CONCLUSIONS: Visual acuity of 20/50 was present in 96% of the patients we examined. Telangiectatic vessels on the bulbar conjunctiva were seen in nearly every patient, though these are of no functional significance. Ocular motor abnormalities, especially strabismus, are a common finding in A-T. Poor accommodation and abnormal eye movements may lead to reading difficulty reported by patients with A-T.

Adolescent↗
PubMed2001

Signal transduction through the B cell antigen receptor is normal in ataxia-telangiectasia B lymphocytes.

The rare human genetic disorder ataxia-telangiectasia (A-T) has multiple consequences including a variable degree of immunodeficiency. Khanna and co-workers (Khanna, K. K., Yan, J., Watters, D., Hobson, K., Beamish, H., Spring, K., Shiloh, Y., Gatti, R. A., and Lavin, M. F. (1997) J. Biol. Chem. 272, 9489-9495) evaluated signaling in Epstein-Barr virus (EBV) immortalized A-T lymphoblastoid cell lines (LCLs), derived from the B cells of A-T patients. They showed that A-T lymphoblastoid cells lack signaling through the B cell antigen receptor and concluded that the fault in A-T encompasses intracellular signaling in B cells. However, it is established that EBV latent membrane protein 2A (LMP2A) blocks signaling in EBV-bearing cells by interaction with cellular tyrosine kinases. To test whether the reported fault in A-T B cells was not inherent in A-T but the result of influence of wild-type EBV, we derived A-T LCLs with wild-type or LMP2A-deleted EBV and studied signaling in these cells in response to cross-linking the B cell antigen receptor. We report that intracellular calcium mobilization and tyrosine phosphorylation in LMP2A-depleted LCLs derived from A-T patients is indistinguishable from that in LMP2A-depleted LCLs derived from normal controls. Further, signaling is blocked similarly in A-T and normal lymphoblastoid cells bearing wild-type EBV. In conclusion there is no evidence of any defect in B cell receptor signal transduction in A-T B cells.

Ataxia Telangiectasia↗