Safety, pharmacokinetics and biological activity of enlimomab (anti-ICAM-1 antibody): an open-label, dose escalation study in patients hospitalized for acute stroke.

BACKGROUND AND PURPOSE: To obtain information on the safety, pharmacokinetics and biological activity of enlimomab (anti-ICAM-1 antibody) in stroke patients. METHODS: An open, uncontrolled, dose titration study was conducted in 32 patients hospitalized for stroke. Patients received one of four fixed dose regimens of enlimomab. A loading dose of enlimomab administered within 24 h of the onset of stroke symptoms was followed by four daily maintenance doses; total doses ranged from 140 to 480 mg. RESULTS: The pharmacokinetic target levels (enlimomab serum levels of >/=10 microg/ml) were consistently achieved in all patients receiving dose regimens III and IV. Non-serious adverse events thought to be causally related to enlimomab administration included headache, vomiting and extrasystoles. Serious events occurred in 14 patients, including pneumonia, sepsis, cardiac failure and cardiac arrest. The only serious adverse event considered to be related to enlimomab administration was an anaphylactoid reaction, in a patient who received an unfiltered loading dose of antibody; the patient recovered. The overall mortality in the study was 15.6% and the 30-day mortality was 12.5%. There was no increase in the frequency of adverse events with increasing doses of enlimomab. CONCLUSIONS: Doses of enlimomab between 140 and 480 mg administered over 5 days did not increase the risk of adverse events in patients with ischaemic or haemorrhagic stroke during an observation period of 30 +/- 10 days. A loading dose of 160 mg followed by four daily maintenance doses of 40 mg appears to be suitable for further study.

Analysis of purine metabolic enzymes in human CD4 Leu 8- and CD4 Leu 8+ lymphocyte subpopulations.

1. Specific activities of adenosine deaminase, purine nucleoside phosphorylase, adenosine kinase, 5'-nucleotidase, S-adenosyl-L-homocysteine hydrolase, AMP deaminase, adenine phosphoribosyl transferase, and hypoxanthine phosphoribosyl transferase were analyzed in human CD4 T-lymphocyte subsets. 2. CD4 Leu 8- (helper/inducer) and CD4 Leu 8+ (suppressor/inducer) subpopulations were obtained by panning or fluorescence activated cell sorting techniques using specific monoclonal antibodies. 3. A 45% decrease of 5'-NT AMP activity in the CD4 Leu 8- cells (suppressor/inducer) compared with CD4 total cell population. 4. No statistical significant differences in enzyme activity were found between the subsets analyzed in other purine enzymes. 5. These results suggest that the distribution of purine metabolic enzymes is homogeneous in CD4 Leu 8- and CD4 Leu 8+ T-lymphocyte subpopulations.

Evolution of sequence divergence among human immunodeficiency virus type 1 isolates derived from a blood donor and a recipient.

Four neonates who were infected with a single unit of blood from a human immunodeficiency virus-1 (HIV-1)-infected adult (patient 1) were studied. Two of the infected children (patients II and III) developed symptomatic HIV-1 disease and died within the first 3 y of life. One child (patient IV) died at 8 mo of age of clinical problems that may have been HIV-related. In contrast, one child (patient V) has remained asymptomatic for 7.5 y and has exhibited a very gradual decline in CD4+ cell number. A previous study had shown very limited sequence diversity of isolates from patients I, II, and III (McNearney T et al.: Proc Natl Acad Sci USA 87:1917-1921, 1990). The current study examined additional HIV-1 sequences encoding the principal neutralizing V3 loop of the surface envelope protein of isolates from patients I and V. Amplified sequences were obtained using the polymerase chain reaction from a cultured isolate and uncultured peripheral blood leukocytes, and nucleotide sequences were determined for 13 clones from patient I and 19 clones from patient V. Clones derived from the cultured isolate exhibited less predicted amino acid sequence diversity on average (0-5.2%) than did sequences from uncultured leukocytes (0-19.8% differences). All clones were more closely related to those from patients II and III (0-19.8% amino acid differences) than to other North American or European isolates (18.8-27.0% amino acid differences) or African isolates (41.0-48.0% amino acid differences). Substitutions occurred at sites predicted to modulate host cell tropism and proteolytic cleavage of the V3 loop.(ABSTRACT TRUNCATED AT 250 WORDS)

A hereditary immunodeficiency characterized by CD8+ T lymphocyte deficiency and impaired lymphocyte activation.

An unusual form of severe combined immunodeficiency in children from two different families was associated with absence of CD8+ T lymphocytes and normal numbers of CD4+ T lymphocytes that did not respond to stimulation by non-specific mitogens, specific antibodies against T cell receptor or specific antigens. The defect in the CD4+ cells was bypassed by activating agents which are independent of the T cell receptor. The combination of an activation defect and selective depletion of CD8+ T lymphocytes suggests that the defective pathway is important in the differentiation of immature thymocytes as well as the proliferation of mature lymphocytes.

The role of the immunologist in sinus disease.

The clinical immunologist is playing an increasingly important role in the evaluation and management of sinus disease. Although most patients with sinus disease are not immunodeficient, a significant proportion of patients with chronic sinusitis unresponsive to medical and/or surgical therapy may have an immunodeficiency. Most immunodeficient patients for whom sinusitis is a major clinical problem tend to be those with humoral immunodeficiency diseases. The role of immunoglobulin replacement therapy is well established for patients with global immunoglobulin and antibody deficiencies (e.g., X-linked agammaglobulinemia and common variable immunodeficiency) and may be helpful in controlling refractory sinusitis in patients with more selective immunoglobulin deficiencies (e.g., IgG subclass deficiency and selective antibody deficiencies), but efficacy in these conditions remains to be established by controlled studies. Many immunodeficient patients have a history of repeated sinus surgery before the recognition of their immune defect. Even in immunodeficient patients treated with antibiotics and immunoglobulin replacement therapy, functional endoscopic sinus surgery is successful in only half of the patients.

Endoscopic ethmoidectomy and maxillary antrostomy in immunodeficient patients.

The efficacy of endoscopic sinus surgery was evaluated in 11 patients with diverse types of primary immunodeficiency disease and symptoms of chronic sinusitis. The postoperative symptoms and ability to eliminate antibiotics were used as outcome parameters. In two patients, the follow-up time was too short to assess therapeutic effectiveness. Five of the remaining nine patients had total or significant resolution of symptoms. Patients with transient immunodeficiency had the best resolution of symptoms. Eight of the total 11 patients were treated with intravenous immunoglobulin preoperatively, and in five patients, the treatment was continued postoperatively. The ability to terminate gamma-globulin reflects not the success of the surgery, but the transient nature of some of the immunodeficiencies.

Subnormal serum concentrations of IgG2 in children with frequent infections associated with varied patterns of immunologic dysfunction.

To characterize more fully the immunologic basis for increased susceptibility to infection in patients with low serum concentrations of IgG2, we identified eight infection-prone children, 1 to 2 years of age, with serum IgG2 concentrations greater than 2 SD below the mean for age and followed their serologic and clinical courses for 1 to 3 years. Two of the eight children became clinically and immunologically normal and may have had transient IgG2 deficiency with an exaggerated developmental delay of this late-maturing subclass. The remaining six subjects had persistently subnormal or low-normal serum IgG2 levels and continued to experience frequent infections. All six of these children responded poorly to Haemophilus influenzae type b (Hib) polysaccharide, and four of six responded poorly to Streptococcus pneumoniae type 3 polysaccharide. Both IgG1 and IgG2-specific antibody responses to these vaccines were abnormal. Three of these six children also responded poorly to tetanus toxoid, an antigen that normally induces a predominant IgG1 response. Although five of these six children produced antibodies in response to Hib polysaccharide protein conjugate vaccine, three of four given Hib oligosaccharide CRM conjugate vaccine required booster doses to respond, a pattern of response characteristic of infants less than 6 months of age. Further, although serum concentrations of IgG1 were normal, peripheral blood mononuclear cells from four of six children tested produced extremely small amounts of IgG1 and IgG3 as well as IgG2. Finally, varied patterns of abnormalities of IgG, IgA, IgM, and IgG4 became apparent in five of the six children with persistently low serum IgG2 values. This study demonstrates that subnormal serum concentrations of IgG2 may be associated with varied patterns of immunologic dysfunction, some of which are evolving and may be responsible for increased susceptibility of these children to infection.

Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycol-modified adenosine deaminase.

We report a 5-year-old girl with adenosine deaminase (ADA) deficiency who was asymptomatic during the first years of life. At 3 years of age, she developed chronic and recurrent sinopulmonary infections, and at 4 1/2 years of age she had one major infection with Streptococcus pneumoniae (bacteremia and septic arthritis of the hip). Immunologic evaluation at 5 years of age revealed persistent lymphopenia, decreased helper-suppressor T cell ratios, and low proliferative responses to mitogens. The IgG, IgM, and IgA levels were normal; the IgG2 level was low normal or below normal. The patient had specific antibodies against toxoids and viral antigens but failed to produce antibodies against Haemophilus influenzae type b and pneumococcal polysaccharides. Although no symptoms of allergy were present, she had persistent eosinophilia and elevated IgE levels. The patient had 0.6% of normal ADA activity in erythrocytes and approximately 1% of normal ADA activity in peripheral blood mononuclear cells. Beginning at 6 years of age, she was treated with weekly injections of polyethylene glycol-modified bovine ADA. This treatment was well tolerated and effectively reversed the biochemical consequence of ADA deficiency. Concomitantly, she improved clinically and her T lymphocyte numbers and blastogenic responses to mitogens in vitro became normal. The late onset of clinical symptoms and relatively benign clinical course in this patient emphasize the need to consider ADA deficiency in a broad spectrum of immunodeficient children.

Cytotoxic factors secreted by cells infected by human immunodeficiency virus type I.

Conditioned media from human immunodeficiency virus type I (HIV-1) infected cells were tested for cytotoxic cell-derived factors. The assay used a murine fibroblast cell line which is sensitive to the effects of tumor necrosis factors, but nonpermissive for HIV-1 replication. Cytotoxic activity was detected in cultures of peripheral blood mononuclear cells infected with HIV-1. However, no differences in activity were found in conditioned media from infected lymphoid or monocytoid cell lines compared to their uninfected counterparts. These data suggest that cytotoxic activities of this type are not mediators of cell killing resulting from HIV-1 infection. Thus, this cytotoxic activity is a direct or indirect result of virus replication or cytopathicity. One should consider a role for this cytotoxic factor, secreted by HIV-1 infected mononuclear cells, in various aspects of infection in vivo, such as AIDS encephalopathy or the systemic manifestations accompanying ARC.

Cartilage hair hypoplasia: immunological aspects and their clinical implications.

Cartilage hair hypoplasia (CHH) is an autosomal recessive form of short-limbed dwarfism prevalent among the Old Order Amish. Mild to moderately severe cellular immunodeficiency is associated with this disorder. Antibody synthesis is, however, normal in CHH. Individuals affected with CHH were found to have marked impairment of T-lymphocyte function due to an intrinsic defect in cell proliferation. Defective proliferation was also found in B cells and fibroblasts from CHH individuals suggesting that impaired T-cell function reflects a generalized defect in cell proliferation in this syndrome. Studies of cytotoxic mechanisms in CHH patients revealed that proliferation-dependent mechanisms (e.g., cell-mediated cytotoxicity and natural killer [NK]-like activity) were markedly impaired while proliferation-independent NK activity was normal. In spite of impairment of T-cell function, an increased incidence of malignancy was not observed in CHH patients. These observations suggest that NK activity is vital in host defense against malignancies and that marked impairment of T-cell-mediated immunity need not be associated with an increased susceptibility to malignancy if NK function is preserved.

Long-term immunological reconstitution by peripheral blood leucocytes in severe combined immune deficiency disease: implications for the role of mature lymphocytes in histocompatible bone marrow transplantation.

A 7 month old girl with severe combined immunodeficiency disease (SCID) received a single transfusion of peripheral blood leucocytes from her histocompatible grandfather in an attempt to achieve immunological reconstitution. There was rapid restoration of humoral and cellular immunity which has persisted undiminished over a 54 month follow-up period and the patient has remained free of any significant infections. Lymphocytes of donor karyotype were repeatedly demonstrated in the patient's peripheral blood. In contrast, no evidence of donor cell engraftment in her bone marrow could be obtained by karyotypic, antigenic or enzyme phenotypic analyses. These observations suggest that long term immunological reconstitution may be achieved solely by peripheral engraftment of mature lymphocytes. A review of the literature reveals that this mechanism of immunological reconstitution may not be uncommon following histocompatible bone marrow transplantation for treatment of SCID.

Anti-IgA antibody associated reactions to intravenous gammaglobulin in a patient who tolerated intramuscular gammaglobulin.

A patient with common variable immunodeficiency syndrome tolerated intramuscular IgG (which contains IgA) and an initial infusion with intravenous (IV) IgG, but developed reactions to subsequent IV IgG. High-titre, class-specific anti-IgA antibodies were detected suggesting immunization by the IgA-contaminated IV immunoglobulin. Subsequent IgG replacement was achieved with IgA-deficient plasma infusions. Patients who tolerate intramuscular IgG may not tolerate the IV preparations.

Spectrum of IgG2 subclass deficiency in children with recurrent infections: prospective study.

Serum immunoglobulins and IgG subclasses were measured in 30 children with recurrent infections. Seven patients had low IgG2 concentrations (less than 3SD below the geometric mean for age). Four of these seven patients had normal concentrations of IgG, IgA and IgM, and thus would have been considered immunologically normal by routine criteria. The seven children with IgG2 deficiency had more severe infections than the 23 children with normal IgG2. Five children had recurrent pneumonia or sinusitis, one had recurrent invasive Haemophilus influenzae type b infections, and one had severe pneumococcal meningitis. Their immunologic abnormalities were heterogeneous. Two children had isolated IgG2 deficiency, two had IgG2-IgG4 deficiency, one had IgG2-IgG4-IgA deficiency, one had IgG2-IgA deficiency, and one had severe IgG1-IgG2 deficiency with abnormal T cell function and thrombocytopenia. Thus IgG2 deficiency occurs frequently among children with recurrent infections, and is associated with a variety of clinical and immunologic abnormalities.

Adenosine induced immunosuppression: the role of the adenosine receptor--adenylate cyclase interaction in the alteration of T-lymphocyte surface phenotype and immunoregulatory function.

Adenosine (1 microM at 37 degrees C) rapidly modulates the expression of T-lymphocyte surface antigens (OKT4 and OKT8) and Fc gamma receptors, and increases T-suppressor activity for pokeweed mitogen driven in vitro immunoglobulin synthesis. The adenosine induced loss of OKT4 expressed was maximal within 5 min, while increased OKT8 expression developed more slowly; increased Fc gamma expression was maximal at 30 min after initiation of incubation with adenosine. Adenosine, 2-chloroadenosine and adenosine in the presence of nitrobenzylthioinosine (NBTI) induced the decrease in OKT4 expression. In contrast only adenosine induced the enhancement of OKT8 and Fc gamma receptor expression. Neither 2-chloroadenosine, a poorly transported analog, nor adenosine in the presence of the adenosine transport inhibitor NBTI were capable of enhancing OKT8 or Fc gamma receptor expression. Adenosine was shown to cause a rapid biphasic increase in cAMP, while 2-chloroadenosine and adenosine with NBTI induces a prolonged elevation in cAMP. Similarly isoproteranol which induces a sustained elevation in cAMP suppressed the adenosine induced increases in OKT8 and Fc gamma receptor expression. Incubation of T-helper/inducer lymphocytes with 1 microM adenosine for 30 min at 37 degrees C caused the loss of T-helper function; this loss of T-helper activity has previously been shown to result from the activation of T-suppressor cells. The loss of T-helper function was blocked by the simultaneous addition of isobutylmethylxanthine, an R site adenosine receptor antagonist, or NBTI, an adenosine transport inhibitor. Moreover, 2-chloroadenosine could not induce loss of T-helper function.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural cytotoxicity in immunodeficiency diseases: preservation of natural killer activity and the in vivo appearance of radioresistant killing.

We studied spontaneous natural killer (NK) cell activity and radiation-resistant NK mediated cytotoxicity in four patients with clinically documented severe combined immune deficiency disease (SCID), and in one subject each with intestinal lymphangiectasia and cartilage-hair hypoplasia. We observed the preservation of spontaneous NK activity in all patients despite the presence of profound B- and T-lymphocytopenia and clinical immunodeficiency. NK activity was associated with relatively normal circulating numbers of OKM1+ lymphocytes, a population known to contain NK effectors. Spontaneous NK activity resistant to 3000 rad was increased in all patients, indicating the presence of activated natural killer cells in vivo. The concept of a chronically activated immune system in these patients was further supported by the presence of increased Ia positive T cells in all subjects tested, suggesting that radioresistant NK activity may be a useful parameter to measure when assessing in vivo immune activation. Our data, as well as that of others, supports the hypothesis that at least one population of NK cells is a distinct lineage arising at the differentiation level of myeloid and lymphoid stem cells in the bone marrow.

Use of intravenous immune globulin in pregnant women with common variable hypogammaglobulinemia.

Two patients with common variable hypogammaglobulinemia were treated with immune serum globulin during pregnancy. An intravenous immune serum globulin preparation was used in the last trimester of pregnancy. Both patients tolerated this preparation well and had an uneventful pregnancy. The two term newborns were healthy and had cord blood IgG levels likely to be the result of transplacental transfer of the intravenous immune serum globulin preparation. During pregnancy there is an increase in the IgG distribution space due to plasma volume expansion. Therefore, pregnancy is an indication for these immune serum globulin preparations that can be administered at high doses intravenously in order to confer adequate protection to the mother and the newborn.

Efficacy and safety of high-dose intravenous immune globulin therapy for antibody deficiency syndromes.

Ten patients with antibody deficiency syndromes were admitted to a treatment protocol in which the dose of intravenous immune serum globulin was increased from 100 mg/kg to a maximum of 250 mg/kg each four weeks. The dose increases were determined by recurrence of infection during treatment and by IgG trough levels of less than 400 mg/dl. Infectious episodes during intravenous immune serum globulin treatment responded well to 10 to 20 day long periods of antibiotic treatment, and prolonged infection-free periods were achieved in all patients. Only one hospital admission was necessary during the entire study period. The increase in intravenous immune serum globulin dose to 200 mg/kg did not significantly reduce the recurrence of infections. Infections also occurred in patients whose IgG trough levels were persistently above 400 mg/dl. High doses of intravenous immune serum globulin were well tolerated, and all patients are still receiving intravenous immune serum globulin treatment. A generalized pruritic rash was observed in two patients. In no patient have clinical or laboratory signs of deficiency in cell-mediated immunity developed.