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The influence of dietary fat on recombinant human tumor necrosis factor-alpha (rHuTNF-alpha)-associated vascular endothelial injury in mice was examined. Histopathologic evaluation showed that greater injury was consistently observed in the uterus characterized by necrosis of endothelial cells lining small vessels in the endometrium and accompanied by multifocal hemorrhage and inflammatory cell accumulation. Mice fed standard animal diet, high corn oil diet, or high menhaden oil diet showed no differences in their susceptibility to the acute injury caused by rHuTNF-alpha injected alone or in combination with recombinant murine interferon-gamma. These results indicate that uterine endothelium may be a more sensitive target for rHuTNF-alpha-mediated endothelial injury and that high menhaden oil diet does not protect against tissue injury associated with the administration of rHuTNF-alpha alone or in combination with recombinant murine interferon-gamma.

The influence of recombinant human TNF-alpha and -beta (rHuTNF-alpha and -beta) in a human mixed lymphocyte reaction (MLR) was investigated. The addition of 1000 U/ml of either cytokine at the initiation of culture caused up to a sixfold increase in [3H]thymidine incorporation by responder cells. Furthermore, it was found that endogenous HuTNF-alpha is produced after allogeneic cell interaction and can be detected in the MLR supernatant within 1 h of culture initiation. The results also show that, in the absence of exogenous HuTNF-alpha, antibodies to rHuTNF-alpha can cause a significant inhibition of the MLR. These observations indicate the importance of TNF-alpha in allogeneic cell interaction and raise considerations for the use of antibodies, or other antagonists, to TNF-alpha as regulators of disease states associated with cell-mediated immune reactions.

Fourteen patients with nasopharyngeal carcinoma were evaluated immunologically prior to standard radiotion therapy. All had elevations of serum IgA, ranging from 300 mg/100 ml to 1000 mg/100 ml, with a mean value of 549 mg/100 ml. Seven patients demonstrated depression of cell-mediated immunity as measured by delayed hypersensitivity skin tests, total lymphocyte count, in vitro stimulation with PHA, and T-cell rosette formation. Elevation of serum IgA associated with depression of cell mediated immunity may be characteristic of patients with nasopharyngeal carcinoma.

The antibody response after immunization with capsular polysaccharides of Streptococcus pneumoniae of patients with Hodgkin's disease or with carcinoma of the head and neck was studied. Patients with Hodgkin's disease who were immunized prior to the institution of immunosuppressive therapy were capable of responding to each of the pneumococcal polysaccharides evaluated. The level of antibody achieved by the patients is lower than that of normal control subjects. Nevertheless, absolute values were in the range that would be expected to result in protection. The duration of antibody response was not evaluated. Patients with carcinoma of the head and neck did not demonstrate a significant increase in antibody levels after vaccination, which was done at the time of radiation therapy. Two years after immunization antibody levels were lower with recovery at three years. However, these changes were not statistically significant. Decreased levels of antibody to pneumococcal polysaccharide types not present in the vaccine were observed. Studies of patients with carcinoma of the heat and neck demonstrated that radiation therapy has a profound immunosuppressive effect on antibody levels. More selective immunosuppressive therapy and/or an increase in the immunogenicity of the polysaccharides in the vaccine are required for protection of patients with malignancy.

Cell-mediated immunity (CMI) in a population of 28 well-nourished, disease-free old-age individuals (65--103 years) was compared to that of healthy young adult controls (22--41 years) and the effects in vitro of thymosin fraction 5 (TF5) evaluated. The number of T cells (T cell rosettes, TCR) in the peripheral blood was the same as controls. However, there was a significant depression in lymphocyte response to phytohemagglutinin (PHA) (p Less Than 0.005). Limiting dilution of the PHA response revealed an inherent defect in the function of those cells that are capable of responding to PHA. The formation of TCR from old-age subjects was similar to controls when incubated with TF5, i.e. there was no enhancement. When TF5 was incubated with old-age and normal control lymphocytes in the mixed lymphocyte reaction (MLR), there were significant increases in the responses in both (71 +/- 39% and 64 +/- 52%, respectively; p Greater Than 0.2). There was also a mitogenic effect of TF5 on resting lymphocytes which was significantly greater in the control than in the old-age population (p Less Than 0.002). Our results suggest that in old age: (1) there is no loss in absolute numbers of T lymphocytes; (2) there is a defect in the ability of individual lymphocytes to function; and (3) the response of lymphocytes in vitro to TF5 in forming TCR and in the MLR is statistically similar to young adult controls, and suggests that the decline in CMI with age is not due to a loss of thymosin-responsive cells.

Purine nucleoside phosphorylase (PNP) deficiency is associated with a severe defect in thymus-derived (T)-lymphocyte function combined with normal bone marrow-derived (B)-lymphocyte function. To investigate the role of this enzyme deficiency in the resulting immune dysfunction, we measured the levels of ribonucleoside and deoxyribonucleoside triphosphates in erythrocytes from two unrelated PNP-deficient, T-lymphocyte-deficient patients. Both PNP-deficient patients have abnormally high levels of deoxyguanosine triphosphate (deoxy-GTP) in their erythrocytes (5 and 8 nmol/ml packed erythrocytes). In contrast, normal controls and adenosine deaminase-deficient, immunodeficient patients do not have detectable amounts of deoxyGTP (<0.5 nmol/ml packed erythrocytes). We propose that deoxyguanosine, a substrate of PNP, is the potentially lymphotoxic metabolite in PNP deficiency. The mechanism of toxicity involves phosphorylation of deoxyguanosine to deoxyGTP, which acts as a potent inhibitor of mammalian ribonucleotide reductase.

Antibody to acquired immunodeficiency syndrome (AIDS)-associated retroviruses (ARVs) was investigated in 68 pediatric patients with abnormalities of T-cell and/or B-cell immunity. All except seven patients conformed to a specific World Health Organization classification for immunodeficiency disease. These seven patients had polyclonal hypergammaglobulinemia and T-cell immunodeficiency. Six of the seven patients had antibody to ARV and had risk factors associated with AIDS. The one patient without antiviral antibody had no AIDS risk factors. No antibody was detected in 61 patients with other primary immunodeficiency disorders. We conclude that ARV first appeared in our population of immunodeficient pediatric patients prior to 1978, is associated with a distinctive immunologic phenotype consisting of polyclonal hypergammaglobulinemia and T-cell immunodeficiency, and does not appear as an opportunistic infection in other immunodeficiency disorders. Detection of the retrovirus associated with AIDS is of value in identifying infants and children who may have unique medical and social problems that occur with AIDS.

The influence of antibodies to recombinant murine tumor necrosis factor-alpha (anti-rMuTNF-alpha) on the development of the graft-versus-host reaction in vivo was investigated. This was done by evaluating the degree of splenomegaly in newborn BDF1 (B6xDBA/2) mice 10-11 days after injection of autologous BDF1 (controls) or semiallogeneic B6 (test) spleen cells. Splenomegaly, as reflected by the spleen index, among test BDF1 mice was 3-4-fold greater than the SI of control BDF1 mice. However, the treatment of test BDF1 mice with multiple injections of rabbit anti-rMuTNF-alpha antiserum resulted in a significant reduction in the SIs. In additional experiments, hamster monoclonal antibodies to rMuTNF-alpha were also shown to be effective in preventing the GVHR in vivo. Neither normal rabbit serum nor normal hamster IgG affected the GVHR in test BDF1 mice. These results indicate that TNF-alpha plays an important role in the development of the GVHR in vivo and suggest that antibodies, or other antagonists, to TNF-alpha may have potential use for the management of organ or tissue transplants.

By using indirect hemagglutination, the antibody responses of normal infants and children to an octavalent pneumococcal vaccine that contained pneumococcal polysaccharide types 1, 3, 6, 7, 14, 18, 19, and 23 were evaluated. By 2 years of age, there was a significant rise in hemagglutination titers to all the polysaccharide types, except type 19. By 6 to 8 months of age, five of the eight types of pneumococcal polysaccharides tested resulted in up to 60% responders and, by 2 years, a significant number responded to all pneumococcal polysaccharide types in the vaccine. Pneumococcal polysaccharide type 3 resulted in a significant antibody response as early as 3 months of age, whereas type 19 never resulted in a significant antibody response. Except for type 3, it seemed that when the other pneumococcal polysaccharides tested produced an antibody response, the degree of resonse did not subsequently change significantly with increasing age. The relationship of antibody response to age for pneumococcal polysaccharides is similar to that found for other polysaccharide vaccines. Based on the results of our study, we would recommend immunization with pneumococcal vaccine at 6 months of age with repeat immunization at 2 years of age, especially in high-risk children.

We investigated the effect of the concentration of type-specific antibody to pneumococcal polysaccharide (PPS) on opsonic requirements for phagocytosis in vitro of Streptococcus pneumonia types 7 and 19. We measured the uptake by human neutrophils of radiolabeled S. pneumoniae opsonized with either complement-intact, complement-depleted (by heat inactivation), or alternative complement pathway-activated (by magnesium dichloride-ethylene glycol tetraacetic acid (MgEGTA) chelation) immune sera with varying concentrations of antibody from individuals immunized with polyvalent PPS vaccine. Increased opsonization was found with increasing concentrations of type-specific antibody in the sera. Higher concentrations of antibody were required to opsonize type 7 than type 19 bacteria, both in the presence and absence of complement activity. Type 19 bacteria were more efficiently opsonized via the alternative complement pathway than type 7. For both types, antibody and the alternative complement pathway provided most of the opsonic activity in sera with lower concentrations of type-specific antibody. At high antibody concentrations, effective opsonization occurred in heat-activated sera, indicating the requirement for complement could be overcome with sufficient amounts of antibody alone.

Three siblings presented in early childhood with central-nervous-system (CNS) dysfunction, candida dermatitis, keratoconjunctivitis, and alopecia. Two were studied immunologically and had absent delayed-hypersensitivity skin-test responses and absent in-vitro lymphocyte responses to candida antigen. One of them had selective IgA deficiency and no antibody response to pneumococcal polysaccharide immunisation, and the other had a subnormal percentage of T lymphocytes in peripheral blood. The first two siblings died with progressive CNS deterioration and overwhelming infection. The third child, who presented with a periorificial candida dermatitis, alopecia, keratoconjunctivitis, and intermittent ataxia at eighteen months of age, had intermittent lactic acidosis and raised excretion of beta-hydroxyproprionate, methylcitrate, beta-methylcrotonylglycine, and beta-hydroxyisovalerate in urine. After four days of oral biotin, 10 mg/per day, the metabolites in her urine were significantly reduced, suggesting a biotin-responsive multiple carboxylase deficiency. These findings, taken with previous reports of immune defects in patients with disorders of branched-chain aminoacid catabolism, suggest a new biochemical basis for primary immunodeficiency disease.

Approximately 40 to 50 infants and children with similar epidemiologic, clinical, and laboratory features of AIDS have been described. The occurrence of significant numbers of patients with PAIDS in geographic areas that are associated with similar risk factors and clinical features of AIDS suggests a common cause. Immunologic evaluation reveals hypergammaglobulinemia, decreased or absent antibody responses after immunization, normal to decreased T-cell numbers, decreased helper/suppressor cell ratios, and abnormal results of functional studies of T-cells. None of the patients described has the clinical or laboratory features of well-established congenital immunodeficiency disorders. No consistent viral agent has been documented except for antibody to ARV and HTLV III. The frequent finding of T-cell abnormalities in the mothers of infants with PAIDS is in contrast to the absence of such abnormalities in the mothers of infants with congenital immunodeficiency disorders. Future studies in PAIDS should be directed toward uncovering the etiology and risk factors as well as determining the response to treatment with various methods of immunologic reconstitution.

A clinical syndrome of transient maculopapular rash with associated eosinophilia, thrombocytopenia, and mild lymphopenia developed in 21 of 35 (60%) neonates receiving both intrauterine transfusions and postnatal exchange transfusions, and six of 17 (35%) neonates receiving multiple exchange transfusions for erythroblastosis fetalis. This syndrome did not develop in infants who received intrauterine transfusions without exchange transfusions or single exchange transfusions without prior intrauterine ones. Patients with this rash and associated laboratory abnormalities did not progress to acute or chronic graft-vs-host disease, and on follow-up examinations were alive and well.

Pediatric acquired immunodeficiency syndrome (PAIDS) results from infection with human immunodeficiency virus (HIV). The majority of infants with AIDS are infected in utero. In most instances, mothers are infected from intravenous drug abuse or bisexual partners. Infected individuals, both mothers and infants, may be asymptomatic for prolonged periods of time. Initially viral replication may be limited and the virus integrated into immune cells. Activation of the virus may result from several factors including infection with other viral agents, such as cytomegalovirus and Epstein-Barr virus. Variable progression of disease may be related to dose of virus, the degree of pre-existing immunodeficiency, and the presence of other infectious agents. Recent evidence suggests that individual HIV isolates vary in their capacity to infect cells. This may explain differences in clinical presentation and progression. A diagnosis of HIV infection may be difficult in infants who have persistence of maternal antibody. Viral isolation is often difficult and unreliable, even in infants who have clinical features of AIDS. Currently only azidothymidine has been shown to reduce viral replication and improve prognosis. However, azidothymidine does not eradicate HIV and patients require repeated or chronic therapy. The drug is not yet approved for use in children, although studies are being performed at several medical centers. Prevention of HIV infection is the single most important approach to controlling its rapid spread in infants. Screening of all blood products by using HIV antibody testing is essential. Increased effort in preventing drug abuse and in reducing pregnancy rates among infected women should be a priority of health care workers.

Seven children and adolescents are described with mixed connective tissue disease. The patients had varying clinical features, commonly characterized by Raynaud phenomenon, arthritis, abnormal pulmonary function, and esophageal dysmotility. All patients had speckled antinuclear antibodies and high titers (greater than 1:100,000) of antibodies to ribonuclease-sensitive extractable nuclear antigen. We prepared extractable nuclear material from radioactively labeled HeLa cells, analogous to classic extractable nuclear antigen. Sera from all seven patients precipitated ribonucleoprotein containing the small nuclear ribonucleic acid species U1 from the HeLa cell extract. Antibody to U1 ribonucleoprotein was not found in sera from 51 of 53 children and adults having a variety of autoimmune and other diseases, nor in sera from nine normal individuals. The U1 ribonucleoprotein appears to be the component of extractable nuclear antigen characteristically reacting with sera from patients with mixed connective tissue disease. The finding of a distinct molecular marker in all children studied with mixed connective tissue disease indicates that this is a distinct disease entity and not a heterogeneous population of immune disorders.

To assess the immunologic status of healthy persons with hemophilia A, we performed studies of T cell immunity in 21 patients, 10 given only cryoprecipitate and 11 given factor VIII concentrate. Patients in the factor VIII group had significantly decreased helper/suppressor T cell ratios. Both groups had diminished mononuclear cell response to phytohemagglutinin and normal mixed lymphocyte culture, compared with controls. Abnormalities in T cell number or function did not correlate with the presence of antibody to cytomegalovirus, Epstein-Barr virus, or hepatitis B. Physicians caring for patients with hemophilia A should realize that asymptomatic individuals may have early evidence of immunodeficiency.

Four infants with skin rash, hepatosplenomegaly, lymphocytosis, eosinophilis, and histiocytic infiltration of the lymph nodes and skin are described; in each of these infants an initial diagnosis of the Letterer-Siwe syndrome was made. Postmortem findings of thymic dysplasia and poorly differentiated, lymphopenic peripheral lympoid tissue in each of the four infants, as well as antimortem clinical findings in one, established a diagnosis of severe combined immunodeficiency. From these and similar cases in the literature, we postulate that the Letterer-Siwe syndrome may not be an unusual presentation of combined immunodeficiency. Appropriate immunologic studies will help to differentiate the two disorders.

Four patients with clinical and laboratory features of the DiGeorge syndrome had a definite history of maternal alcoholism. Certain clinical abnormalities in the patients were characteristic of the DiGeorge syndrome as well as the fetal alcohol syndrome, including abnormalities of the eyes, ears, mouth, face, cardiovascular system, CNS, and immune system. Maternal alcoholism may result in the DiGeorge syndrome either as the single causative factor or in conjunction with other as yet unknown teratogens.

Behcet syndrome, a multisystem disorder characterized by ocular, mucocutaneous, articular, vascular, gastrointestinal, and neurologic abnormalities, is described in six pediatric patients. The patients ranged in age from 2 months to 11 years at time of onset. Several years were usually required before additional manifestations of the disease occurred. Aphthous ulceration was present in all six patients, arthritis in three, erythema nodosum in four, sterile cellulitis in three, gastrointestinal manifestations in five, neurologic manifestations in two, and genital or perianal ulcerations in three; ocular involvement was present in only one. There were no diagnostic laboratory studies, and, as in the adult population, no cause for Behçet syndrome was found. Patients had a variable response to corticosteroid therapy. Two patients who had significant morbidity and who responded poorly to corticosteroid therapy also received chlorambucil therapy, which appeared to provide improved control of signs and symptoms. Based on the prolonged interval between onset and the appearance of complete manifestations, Behcet syndrome may be more common in children than previously reported.

Sjögren syndrome, consisting of keratoconjunctivitis sicca and xerostomia with or without another autoimmune disease, is uncommon in children. We describe our retrospective experience with eight pediatric patients with SS. All had recurrent parotid enlargement and abnormal salivary gland biopsies, six had keratoconjunctivitis sicca, and five had other autoimmune manifestations, although only two of these had other clearly defined autoimmune disorders (mixed connective tissue disease and hypergammaglobulinemic purpura). Our patients had a higher incidence of primary SS, parotid enlargement, and hematologic abnormalities than did children previously reported with SS. Children with SS demonstrate a clinical heterogeneity comparable to that seen in adults.

An infant who received multiple transfusions during the first few days of life for rhesus disease became ill with recurrent infections when 6 months old. Hepatitis, thrush, Candida dermatitis, otitis media, and disseminated Mycobacterium avium intracellulare infection occurred by 14 months of age. Immunological studies showed raised immunoglobulin levels, decreased mononuclear-cell responses to allogeneic cells and mitogen, and a decreased helper/suppressor cell ratio. It was determined that one of the blood donors, who was well at the time of blood donation, had died 17 months after with multiple opportunistic infections and acquired immunodeficiency. The clinical and laboratory findings in our patient suggest that he acquired a transmissible infectious agent from a blood transfusion, resulting in acquired immunodeficiency, and that this agent was not cytomegalovirus, Epstein-Barr virus, or hepatitis B virus.

This report summarizes the spectrum of clinical and immunologic findings gathered prospectively in 13 patients with the DiGeorge syndrome. Our patients demonstrated marked variability in both the clinical manifestations and the degree of immunodeficiency, confirming the findings of earlier individual case reports and retrospective autopsy reviews. Ages at the time of presentation ranged from one day to 4 months. Congenital heart defects including truncus arteriosus, ventricular septal defect, interrupted aortic arch, and tetralogy of Fallot commonly brought these infants to medical attention within the first two weeks of life. Abnormal calcium homeostasis was found in all patients. Those patients presenting after the first month of life often had hypocalcemic seizures as the initial clinical manifestation. Parathyroid hormone levels and the number and location of parathyroid glands varied considerably. Immunologic evaluation revealed that total lymphocyte counts, percent T-cells, total T-cells, and T-lymphocyte function ranged from normal to severely depressed. The most consistent immunologic abnormality, found in 11 of the 13 patients, was a decrease in total T-cells. Sequential studies in five patients demonstrate that spontaneous resolution of immunodeficiency may occur in some, yet progressive loss of immune function may be observed in others. Complete immunologic evaluation and careful followup is mandatory in infants with persistent hypocalcemia and congenital heart disease who are suspected to have DiGeorge syndrome.

The serum immunoglobulin-A level was elevated in patients with nasopharyngeal carcinoma (mean 526 plus or minus 188 mg/100 ml) and paranasal sinus carcinoma (mean 451 plus or minus 124 mg/100 ml) prior to radiation therapy. After treatment, the IgA levels were lower in nasopharyngeal carcinoma patients. Elevated serum IgA values were also noted in patients with recurrent nasopharyngeal carcinoma. Serum IgA determinations may be useful as an additional diagnostic test for squamous cell carcinoma of the nasal and oropharynx.

Acquired immune deficiency syndrome (AIDS) has been reported in previously healthy homosexual or bisexual males, intravenous drug users, heterosexual men with hemophilia, and Haitians. The finding of heterosexual hemophiliacs with AIDS has raised the possibility of a transmittable blood-borne agent as a cause of this disease. We have found three female half-siblings who had clinical and laboratory evidence for AIDS. All three had evidence of abnormal in vitro cellular immunity; two had chronic active Epstein-Barr virus infection and lymphadenopathy; all three had chronic cutaneous Candida sp infection; and two had Pneumocystis carinii pneumonia. Their mother is a prostitute/drug addict with abnormal T-cell immunity including clinical and laboratory findings of mucocutaneous candidiasis. Histocompatibility typing is consistent with the history of different fathers for each child. Immunologic studies in one child evaluated prospectively from birth were abnormal by 2 months of age. These findings and the clinical histories indicate AIDS and strongly suggest vertical transmission of an agent(s) during the perinatal period.

The ontogeny of human antibody responses to pneumococcal polysaccharide antigens was studied by determining whether the age at immunization affects the level and/or immunoglobulin isotype of antibody produced. Twenty-nine healthy infants between 2 and 18 months of age and 13 normal adults were studied. Responses were found to vary markedly with the age at the time of immunization and with the pneumococcal serotype tested. Three general patterns of isotype-specific antibody response were observed in the infants: a high response in IgG antibody occurred as early as 2 months of age following immunization with type 3 pneumococcal polysaccharide; little or no response was noted in either IgG or IgM antibody with types 6, 18, and 19; and intermediate responses with IgM antibody increases greater than IgG increases were found for type 23. These data suggest that different factors control the immunologic response of infants to various pneumococcal polysaccharide serotypes following immunization at various ages.

To evaluate further the immunodeficiency of homosexual men, blood and lymph node specimens were obtained from five homosexual men with lymphadenopathy and from seven homosexual men with Kaposi's sarcoma. Monoclonal antibodies were used to identify T-lymphocyte subsets in blood by cytofluorometry and in frozen sections of nodes by immunoperoxidase techniques. The homosexuals with Kaposi's sarcoma had a T-helper/suppressor ratio in blood of 0.7; the homosexuals with lymphadenopathy had a ratio of 0.6, compared with controls of 2.1. Control lymphoid tissue had a ratio of 3.0 in the interfollicular areas compared with the reactive lymph nodes in the homosexuals with lymphadenopathy, which was 0.7, and nodes from patients with Kaposi's sarcoma, 0.9. The nodes from homosexual men had evident numerous suppressor cells in the follicular center and mantle regions, locations in normal lymphoid tissue where suppressor cells were uncommon.

An extract of calf thymus, thymosin, induces an increase in percentage of T-cell rosettes when incubated in vitro with sheep erythrocytes and lymphocytes from patients with primary immunodeficiency diseases or viral illness. Precursor lymphocytes are required for this increase to occur. The percentage of T-cell rosettes, when they are normal, is not increased further upon incubation with thymosin. A patient with thymic hypoplasia and immunoglobulin synthesis was selected to receive thymosin in vivo when her T-cell rosettes had increased from 15 to 48 per cent after in vitro incubation with thymosin. During therapy, she clinically improved, the percentage of T-cell rosettes gradually increased to normal, and positive delayed hypersensitivity skin tests developed. Thymosin may be useful clinically for partial reconstitution of cellular immunity. An increased percentage of T-cell rosettes after incubation with thymosin in vitro may predict which patients will respond to thymosin therapy in vivo.