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Purpose Metabolic detoxification with enzyme replacement therapy (ERT) promotes immune recovery in patients with adenosine deaminase (ADA)–deficient severe combined immunodeficiency (ADA-SCID). Elapegademase is a PEGylated recombinant bovine ADA ERT developed to replace the now-discontinued bovine-derived pegademase. This study was a 1-way crossover from pegademase to elapegademase in 7 patients with ADA-SCID to assess efficacy and safety outcomes for elapegademase. Methods After once-weekly pegademase dosage was adjusted to achieve therapeutic metabolic detoxification and trough ADA activity, patients transitioned to a bioequivalent dose of elapegademase. Maintenance of metabolic detoxification and adequate ADA activity were evaluated periodically. Results One patient withdrew after 2 doses of an early elapegademase formulation due to injection-site pain caused by EDTA. The 6 remaining patients completed 71−216 weeks of elapegademase therapy with a formulation that did not contain EDTA. In these patients, elapegademase improved ADA activity compared with pegademase and maintained metabolic detoxification. Total lymphocyte counts increased for all completer patients from between 1.2- and 2.1-fold at the end of study compared with baseline. Elapegademase had a comparable safety profile to pegademase; no patient developed a severe infectious complication. Three patients had transient, non-neutralizing antibodies to pegademase, elapegademase, and/or polyethylene glycol ≤ 47 weeks of treatment without effect on trough plasma ADA activity or trough erythrocyte deoxyadenosine nucleotide levels. Conclusion Elapegademase was safe, well tolerated, achieved stable trough plasma ADA activity with weekly dosing, was effective in maintaining metabolic detoxification, and was associated with maintenance or improvements in lymphocyte counts compared with pegademase therapy in patients with ADA-SCID.

Increasingly, genomics is informing clinical practice, but challenges remain for medical professionals lacking genetics expertise, and in access to and clinical utility of genomic testing for minority and underrepresented populations. The latter is a particularly pernicious problem due to the historical lack of inclusion of racially and ethnically diverse populations in genomic research and genomic medicine. A further challenge is the rapidly changing landscape of genetic tests and considerations of cost, interpretation, and diagnostic yield for emerging modalities like whole-genome sequencing.The NYCKidSeq project is a randomized controlled trial recruiting 1130 children and young adults predominantly from Harlem and the Bronx with suspected genetic disorders in three disease categories: neurologic, cardiovascular, and immunologic. Two clinical genetic tests will be performed for each participant, either proband, duo, or trio whole-genome sequencing (depending on sample availability) and proband targeted gene panels. Clinical utility, cost, and diagnostic yield of both testing modalities will be assessed. This study will evaluate the use of a novel, digital platform (GUÍA) to digitize the return of genomic results experience and improve participant understanding for English- and Spanish-speaking families. Surveys will collect data at three study visits: baseline (0 months), result disclosure visit (ROR1, + 3 months), and follow-up visit (ROR2, + 9 months). Outcomes will assess parental understanding of and attitudes toward receiving genomic results for their child and behavioral, psychological, and social impact of results. We will also conduct a pilot study to assess a digital tool called GenomeDiver designed to enhance communication between clinicians and genetic testing labs. We will evaluate GenomeDiver's ability to increase the diagnostic yield compared to standard practices, improve clinician's ability to perform targeted reverse phenotyping, and increase the efficiency of genetic testing lab personnel.The NYCKidSeq project will contribute to the innovations and best practices in communicating genomic test results to diverse populations. This work will inform strategies for implementing genomic medicine in health systems serving diverse populations using methods that are clinically useful, technologically savvy, culturally sensitive, and ethically sound.ClinicalTrials.gov NCT03738098 . Registered on November 13, 2018 Trial Sponsor: Icahn School of Medicine at Mount Sinai Contact Name: Eimear Kenny, PhD (Principal Investigator) Address: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl., Box 1003, New York, NY 10029 Email: eimear.kenny@mssm.edu.

Background Increasingly, genomics is informing clinical practice, but challenges remain for medical professionals lacking genetics expertise, and in access to and clinical utility of genomic testing for minority and underrepresented populations. The latter is a particularly pernicious problem due to the historical lack of inclusion of racially and ethnically diverse populations in genomic research and genomic medicine. A further challenge is the rapidly changing landscape of genetic tests and considerations of cost, interpretation, and diagnostic yield for emerging modalities like whole-genome sequencing. Methods The NYCKidSeq project is a randomized controlled trial recruiting 1130 children and young adults predominantly from Harlem and the Bronx with suspected genetic disorders in three disease categories: neurologic, cardiovascular, and immunologic. Two clinical genetic tests will be performed for each participant, either proband, duo, or trio whole-genome sequencing (depending on sample availability) and proband targeted gene panels. Clinical utility, cost, and diagnostic yield of both testing modalities will be assessed. This study will evaluate the use of a novel, digital platform (GUÍA) to digitize the return of genomic results experience and improve participant understanding for English- and Spanish-speaking families. Surveys will collect data at three study visits: baseline (0 months), result disclosure visit (ROR1, + 3 months), and follow-up visit (ROR2, + 9 months). Outcomes will assess parental understanding of and attitudes toward receiving genomic results for their child and behavioral, psychological, and social impact of results. We will also conduct a pilot study to assess a digital tool called GenomeDiver designed to enhance communication between clinicians and genetic testing labs. We will evaluate GenomeDiver’s ability to increase the diagnostic yield compared to standard practices, improve clinician’s ability to perform targeted reverse phenotyping, and increase the efficiency of genetic testing lab personnel. Discussion The NYCKidSeq project will contribute to the innovations and best practices in communicating genomic test results to diverse populations. This work will inform strategies for implementing genomic medicine in health systems serving diverse populations using methods that are clinically useful, technologically savvy, culturally sensitive, and ethically sound. Trial registration ClinicalTrials.govNCT03738098. Registered on November 13, 2018 Trial Sponsor: Icahn School of Medicine at Mount Sinai Contact Name: Eimear Kenny, PhD (Principal Investigator) Address: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl., Box 1003, New York, NY 10029 Email: eimear.kenny@mssm.edu

Purpose Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies. Methods Subjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule. Results Eighty-three subjects (24

Quantification of T-cell receptor excision circles (TRECs) for newborn screening for SCID has advanced the diagnosis of severe combined immune deficiency (SCID). However, it has led to the identification of infants with T cell lymphopenia without known cause. The clinical characteristics, appropriate laboratory monitoring, and outcomes of patients remain unclear. We performed a retrospective review of clinical and laboratory studies for 26 infants collected from 7 New York State referral centers from 2010 to 2016 with low TRECs (mean, 70 copies/μl) and subnormal CD3 counts (mean, 1150/cubic mm). Over time absolute CD3 counts increased in 17 and decreased in 9; 22 (85%) have done well clinically regardless of absolute T cell values. Additional infants with TCL will continue to be identified in newborn screening panels. While most patients seem to do well clinically, parameters for diagnosis and monitoring have yet to be formalized, and additional information needs to be collected, causes and outcomes reported.

To describe the process and assess outcomes for the first 2 years of newborn screening for severe combined immunodeficiency (SCID NBS) in New York State (NYS).The NYS algorithm utilizes a first-tier molecular screen for TRECs (T-cell receptor excision circles), the absence of which is indicative of increased risk of immunodeficiency.During the first 2 years, 485,912 infants were screened for SCID. Repeat specimens were requested from 561 premature and 746 non-premature infants with low or borderline TRECs. A total of 531 infants were referred for diagnostic evaluation leading to identification of 10 infants with SCID and 87 with a clinically significant non-SCID abnormality based on flow cytometry or CBC results (positive predictive value 20.3 %). Nine infants were diagnosed with typical SCID and one with leaky SCID. SCID diagnoses included two patients with adenosine deaminase deficiency, three patients with typical and one with leaky IL2RG-related SCID, one patient with IL7Rα-related SCID, and three cases of typical SCID, etiology unknown. TRECs were undetectable in eight of the nine babies with typical SCID. Infants with other non-SCID conditions included 27 patients with a syndrome that included T-cell impairment, 18 of which had DiGeorge syndrome. Seventeen infants had T-cell impairment secondary to another clinically significant condition, and 13 were classified as 'other'. Among 30 infants classified as idiopathic T-cell lymphopenia, 11 have since resolved, and the remainder continues to be followed. One infant with undetectable TRECs had normal follow-up studies. Molecular studies revealed the presence of two changes in the infant's DNA.Overall, ten infants with SCID were identified during the first 2 years of screening in NYS, yielding an incidence of approximately 1 in 48,500 live births, which is consistent with the incidence observed by other states screening for SCID. The incidence of any clinically significant laboratory abnormality was approximately 1 in 5,000; both estimates are higher than estimates prior to the onset of newborn screening for SCID. Improvements to the NYS algorithm included the addition of a borderline category that reduced the proportion of infants referred for flow cytometric analysis, without decreasing sensitivity. We identified a large number of infants with abnormal TRECs and subsequent idiopathic T-cell lymphopenia. Long-term follow-up studies are needed to determine the prognosis and optimal treatment for this group of patients, some of whom may present with previously unrecognized, transient lymphopenia of infancy.

Background: Necrobiotic xanthogranuloma (NXG) is a rare chronic disorder characterized by firm yellow to red-orange nodules and plaques affecting the face, abdomen, and extremities with the potential for systemic involvement. NXG has a close association with monoclonal gammopathies, and there is a predilection for the development of multiple myeloma. Treatment options are varied due to inconsistent results seen with the use of corticosteroids, immunomodulators, chemotherapeutic agents, and antibiotics. Objective: We describe a patient with smoldering multiple myeloma associated with progressive NXG successfully treated with high-dose intravenous immunoglobulin (IVIG). Conclusion: Our case adds to the single previous report of two cases of NXG with significant improvement from treatment with IVIG and confirms the efficacy of this treatment modality.

Background Obesity-associated asthma has been proposed to be a distinct entity, differing in immune pathogenesis from atopic asthma. Both obesity-mediated inflammation and increase in adiposity are potential mechanistic factors that are poorly defined among children. We hypothesized that pediatric obesity-associated asthma would be characterized by T helper (Th) 1, rather than the Th2 polarization associated with atopic asthma. Moreover, we speculated that Th1 biomarkers and anthropometric measures would correlate with pulmonary function tests (PFTs) in obese asthmatic children. Methods We recruited 120 children, with 30 in each of the four study groups: obese asthmatic children, nonobese asthmatic children, obese nonasthmatic children, and nonobese nonasthmatic children. All children underwent pulmonary function testing. Blood was collected for measurement of serum cytokines. T-cell responses to mitogen, phorbol 12-myristate 13-acetate (PMA), or antigens tetanus toxoid or Dermatophagoides farinae were obtained by flow cytometric analysis of intracellular cytokine staining for interferon-γ (IFN-γ) (Th1) or IL-4 (Th2) within the CD4 population. Results Obese asthmatic children had significantly higher Th1 responses to PMA (P Conclusions We found that pediatric obesity-associated asthma differed from atopic asthma and was characterized by Th1 polarization. The altered immune environment inversely correlated with PFTs in obese asthmatic children.

While it is well known that patients with common variable immunodeficiency (CVID) are predisposed to various malignancies, primarily non-Hodgkin’s lymphoma and gastric carcinomas, to our knowledge no cases of hepatocellular carcinoma have been reported in the absence of preexisting liver disease. We report a 50-year-old male patient with CVID with a B- and T-cell deficiency. The patient was on prophylactic intravenous gammaglobulin and had received several years earlier a course of rituximab for an autoimmune disorder. He had no history of hepatitis. The patient developed a rapidly progressing hepatocellular carcinoma within 3 to 4 weeks. Although patients with CVID are predisposed to malignancies such as lymphoma and adenocarcinoma of the stomach, rapidly progressive hepatocellular carcinoma in the absence of any preexisting liver disease has not been described.

A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune-mediated process and the role of autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16-year-old female who was diagnosed with acute-onset non-neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti-GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune-mediated limbic encephalitis and immune deficiency.

The HIV-1 epidemic continues to spread at a rate of over 15, 000 new cases daily. HIV-1 transmission through heterosexual contact became the dominant risk for women globally. About half of the over 40 million HIV-1 infected individuals worldwide are now women. The lack of empowerment of women is the fundamental cause for the rampant spread of HIV-1 in women. Topical microbicides applied intravaginally offer an option for female-initiated HIV-1 prevention. There is an urgent need to develop microbicides with and without contraceptive qualities to also address socio-cultural settings where the woman's status is linked to fertility. A safe and efficacious anti-HIV-1 vaginal formulation is not yet available though a large number of candidates are in preclinical or clinical studies. Presently marketed topical microbicides are by and large toxic and damage the vaginal mucosa with frequent use. The microbicidal system of alkylureas evaluated here lends itself to contraceptive and non-contraceptive anti- HIV-1 formulations. Alkylureas are agents that irreversibly disrupt free and intracellular HIV-1, have a wide margin of safety and are spermicidal above their virucidal concentration without any mucosal toxicity. Butylurea, the lead compound is also effective against other sexually transmitted diseases (STDs) while sparing the normal vaginal flora. Alkylureas with longer alkyl chains still have to be explored and may have a greater selective microbicidality.

Objective: Our objective was to examine the influence of pregnancy on human immunodeficiency virus type 1 viral load by measuring human immunodeficiency virus type 1 ribonucleic acid levels during pregnancy and post partum. Study Design: One or more plasma or serum specimens obtained before and during the third trimester, and at 2, 12, and 24 months post partum were available for 160 human immunodeficiency virus type 1-seropositve women enrolled in the Mothers and Infants Cohort Study between January 1986 and January 1991. All specimens were frozen and stored at −70°C until analyzed in batch for human immunodeficiency virus type 1 ribonucleic acid by polymerase chain reaction. A multivariate longitudinal random effects model was developed to examine changes in human immunodeficiency virus type 1 ribonucleic acid levels over time. Results: Overall, human immunodeficiency virus type 1 ribonucleic acid levels rose significantly during the study period, particularly during the second year post partum (mean, 0.09 log per year; 95% confidence interval, 0.03 to 0.15 logs per year; p =0.005). However, the mean slope during pregnancy was not significantly different from zero ( p =0.65). Conclusion: Pregnancy had little immediate effect on human immunodeficiency virus type 1 viral load in most human immunodeficiency virus type 1-seropositive women.

Objectives: The passage of immunoglobulin G (IgG) across the placenta is thought to involve Fc’ receptors on the syncytiotrophoblast. To confirm the receptor dependency of this process we have studied the changes in the tissue content and transfer kinetics of immunoglobulins and hyperimmune serum to HIV (HIVIG) during in vitro dual placental perfusion. Methods: Isolated lobules of term placentae from normal pregnancies were perfused in a model of maternal and fetal circulation. The perfused tissue was compared to fresh tissue samples from the same placenta for the content of IgG, IgG subclasses, IgM, cytokeratin, human placental lactogen and SP1 antigen by immunohistochemistry and by protein elution. Results: The immunoglobulin staining faded by an average of 40% during the 1st hour of perfusion. In contrast, staining for cytokeratin, human placental lactogen and SP1 remained unchanged. During a 4-hour recycling of endogenous immunoglobulins in the maternal circulation, IgG and HIVIG crossed to the fetal side in a steady rate. The transport of HIVIG could be inhibited by preperfusion with an intravenous gammaglobulin preparation (IVIG). Discussion: The transfer of IgG across the placenta occurs in a steady state rate consistent with a receptor-mediated mechanism. Furthermore, inhibition of HIVIG maternofetal transfer by IVIG further establishes the receptor-mediated transfer of immunoglobulins through the placenta.

Objective. To determine the timing, extent, severity, and persistence of neurologic abnormalities in children with perinatally acquired human immunodeficiency virus 1 (HIV-1) infection compared with similar uninfected children of HIV-1-infected women and control children. Methods. Serial neurologic examinations and head circumference measurements were performed on a cohort of HIV-1-infected children born to HIV-1-infected women, seroreverting children born to HIV-1-infected women, and control children born to uninfected women. Examination data from 32 HIV-1-infected children, 99 reverters, and 116 control children were summarized by eight neurologic domains. Data were analyzed by longitudinal analysis. Results. Reverter children were not different from control children in neurologic function for any of the eight domains or head circumference. HIV-1-infected children had significantly more neurologic problems than the control and reverter children for seven of the eight domains. The HIV-1-infected children were further classified by whether they had acquired immunodeficiency syndrome (AIDS)-defining clinical conditions (other than lymphoid interstitial pneumonitis) in the first 24 months of life (the AIDS-opportunistic infection group) or did not (the infected-other group). Neurologic abnormalities were early, severe, pervasive, and persistent in the AIDS-opportunistic infection group, and nearly all in this group had head circumference measurements below the 10th percentile. The infected-other group had no statistically significant differences from the uninfected children, although individual children in the infected-other group had some abnormalities. Conclusions. In utero exposure to HIV-1 without infection seems to have no negative impact on neurologic function in children in the first 2 years of life. Among children with perinatally acquired HIV-1 infection, the most severe and pervasive neurologic problems occur in those children who have early serious HIV-1 clinical disease. Most children without serious AIDS-defining clinical conditions in the first 2 years of life are also free from serious neurologic problems during that period.

OBJECTIVE: Our objective was to examine changes in CD4 + and CD8 + cell levels during pregnancy and post partum and to determine whether they differ for human immunodeficiency virus-1–seropositive and seronegative women. STUDY DESIGN: A total of 192 human immunodeficiency virus-1 – seropositive and 148 seronegative women enrolled in a study of mother-to-child transmission of human immunodeficiency virus-1 who had at least two lymphocyte subset measurements performed during pregnancy or post partum were included in this analysis. Mixed effects repeated-measures models were developed to examine changes in CD4 + and CD8 + cell levels during this period. RESULTS: Consistent with prior reports that CD4 + cell levels decline during pregnancy and return to normal post partum, percent levels increased between the third trimester and 12 months post partum among human immunodeficiency virus – seronegative women (1.98%, p = 0.04). However, CD4 + levels declined steadily during pregnancy and post partum among seropositive women (−1.57%, p = 0.02 between the third trimester and 12 months post partum; −2.65%, p = 0.0004 between 2 and 24 months post partum). The percent CD8 + cell levels increased at or near delivery and declined to baseline between 2 and 6 months post partum in both seronegative and seropositive women, although only the declines were statistically significant in both groups (−2.66%, p = 0.004; and −2.02%, p = 0.02, respectively). CONCLUSIONS: The percent CD4 + cell levels declined steadily during pregnancy and post partum among human immunodeficiency virus - seropositive women, indicating that human immunodeficiency virus disease continues to progress during this period. The percent CD8 + cell levels increased at or near delivery and declined to baseline post partum in both seronegative and seropositive women. These findings may have important clinical implications for both human immunodeficiency virus - infected and uninfected pregnant women. (AM J OBSTET GYNECOL 1996;174:1461-8.)

The current dosage of zidovudine for children is 180 mg/m2 every 6 h. To investigate whether a lower dosage was equally effective, human immunodeficiency virus (HIV)-infected children (3 months to 12 years) with mild to moderate symptoms were randomly assigned to receive either high-dose (180 mg/m2/dose) or low-dose (90 mg/m2/dose) zidovudine (double-blind). Treatments were compared with respect to neuropsychologic function, survival, clinical and laboratory evidence of disease progression, and safety and tolerance. Four hundred twenty-six HIV-infected children were enrolled; median time for receipt of study drug was 35 months. Zidovudine in either dose was well tolerated, with no difference in efficacy or tolerance by treatment group using any clinical or laboratory parameter. In children with mild to moderate disease, a reduction of zidovudine to 90 mg/m2/dose will result in substantial cost savings and should be the recommended dose.

Drugs that reduce viral production or prevent viral spread by interference with the host's cellular components are unlikely to induce resistance, in contrast to treatment modalities that interact with the HIV-1 life cycle. Two features make L-cycloserine (L-CS) a candidate drug of this kind: (a) L-CS is a potent inhibitor of the sphingolipid pathway (b) sphingolipids, galactocerebrosides, and sulfatides have been shown, by others, to bind gp120. In a feasibility and efficacy study, we have found that L-CS inhibits HIV-1 replication in a CD4+ lymphoid cell line (CEM) as documented by the reduction of syncytium formation, the number of HIV-1 infected cells, and p24 protein production. This observation may lead to a new strategy for the treatment of HIV-1 infection.

Neuronal cells in culture respond to neuronal growth factors by secondary cellular pathways similar to those described for activation of lymphocytes and macrophages. In HIV-1-infected T lymphocytes and in macrophages, these pathways were shown to converge on nuclear factors that bind and stimulate the HIV-1 LTR and lead to enhancement of HIV-1 expression. In the current study we have investigated whether the same mechanisms also enhance HIV-1 production by neural cells. We have demonstrated that HIV/N1T replication in HCN-1A cells, a human cortical neuronal cell line, is enhanced threefold by nerve growth factor (NGF) and by fibroblast growth factor (FGF), but not by epidermal growth (EGF) factor, or phorbol ester. HCN-1A cells also responded to HIV/N1T infection with pronounced morphological changes, indicative of a differentiation-like process. The cells diminished in size and small neurites were observed.

A small animal model that could be infected with human immunodeficiency virus 1 (HIV-1) after peripheral inoculation would greatly facilitate the study of the pathophysiology of acute HIV-1 infection. The utility of SCID mice implanted with human fetal thymus and liver (SCID-hu mice) for studying peripheral HIV-1 infection in vivo has been hampered by the requirement for direct intraimplant injection of HIV-1 and the continued restriction of the resultant HIV-1 infection to the human thymus and liver (hu-thy/liv) implant. This may have been due to the very low numbers of human T cells present in the SCID-hu mouse peripheral lymphoid compartment. Since the degree of the peripheral reconstitution of SCID-hu mice with human T cells may be a function of the hu-thy/liv implant size, we increased the quantity of hu-thy/liv tissue implanted under the renal capsule and implanted hu-thy/liv tissue under the capsules of both kidneys. This resulted in SCID-hu mice in which significant numbers of human T cells were detected in the peripheral blood, spleens, and lymph nodes. After intraimplant injection of HIV-1 into these modified SCID-hu mice, significant HIV-1 infection was detected by quantitative coculture not only in the hu-thy/liv implant, but also in the spleen and peripheral blood. This indicated that HIV-1 infection can spread from the thymus to the peripheral lymphoid compartment. More importantly, a similar degree of infection of the hu-thy/liv implant and peripheral lymphoid compartment occurred after peripheral intraperitoneal inoculation with HIV-1. Active viral replication was indicated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced tat/rev RNA in the hu-thy/liv implants, peripheral blood mononuclear cells (PBMC), spleens, and lymph nodes of these HIV-1-infected SCID-hu mice. As a first step in using our modified SCID-hu mouse model to investigate the pathophysiological consequences of HIV-1 infection, the effect of HIV-1 infection on the expression of human cytokines shown to enhance HIV-1 replication was examined. Significantly more of the HIV-1-infected SCID-hu mice expressed mRNA for human tumor necrosis factors alpha and beta, and interleukin 2 in their spleens, lymph nodes, and PBMC than did uninfected SCID-hu mice. This suggested that HIV-1 infection in vivo can stimulate the expression of cytokine mRNA by human T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Obesity-associated asthma has been proposed to be a distinct entity, differing in immune pathogenesis from atopic asthma. Both obesity-mediated inflammation and increase in adiposity are potential mechanistic factors that are poorly defined among children. We hypothesized that pediatric obesity-associated asthma would be characterized by T helper (Th) 1, rather than the Th2 polarization associated with atopic asthma. Moreover, we speculated that Th1 biomarkers and anthropometric measures would correlate with pulmonary function tests (PFTs) in obese asthmatic children.We recruited 120 children, with 30 in each of the four study groups: obese asthmatic children, nonobese asthmatic children, obese nonasthmatic children, and nonobese nonasthmatic children. All children underwent pulmonary function testing. Blood was collected for measurement of serum cytokines. T-cell responses to mitogen, phorbol 12-myristate 13-acetate (PMA), or antigens tetanus toxoid or Dermatophagoides farinae were obtained by flow cytometric analysis of intracellular cytokine staining for interferon-γ (IFN-γ) (Th1) or IL-4 (Th2) within the CD4 population.Obese asthmatic children had significantly higher Th1 responses to PMA (P.01) and tetanus toxoid (P.05) and lower Th2 responses to PMA (P.05) and D farinae (P.01) compared with nonobese asthmatic children. Th-cell patterns did not differ between obese asthmatic children and obese nonasthmatic children. Obese asthmatic children had lower FEV(1)/FVC (P.01) and residual volume/total lung capacity ratios (P.005) compared with the other study groups, which negatively correlated with serum interferon-inducible protein 10 and IFN-γ levels, respectively. PFTs, however, did not correlate with BMI z score or waist to hip ratio.We found that pediatric obesity-associated asthma differed from atopic asthma and was characterized by Th1 polarization. The altered immune environment inversely correlated with PFTs in obese asthmatic children.