Publications

The Tax oncoprotein of the type I human T cell leukemia virus (HTLV-I) activates transcription of cellular and viral genes through at least two different transcription factor pathways. Tax activates transcription of the c-fos proto-oncogene by a mechanism that appears to involve members of the cAMP response element binding protein (CREB) and activating transcription factor (ATF) family of DNA-binding proteins. Tax also induces the nuclear expression of the NF-kappa B family of rel oncogene-related enhancer-binding proteins. We have investigated the potential role of these CREB/ATF and NF-kappa B/Rel transcription factors in Tax-mediated transformation by analyzing the oncogenic potential of Tax mutants that functionally segregate these two pathways of transactivation. Rat fibroblasts (Rat2) stably expressing either the wild-type Tax protein or a Tax mutant selectively deficient in the ability to induce NF-kappa B/Rel demonstrated marked changes in morphology and growth characteristics including the ability to form tumors in athymic mice. In contrast, Rat2 cells stably expressing a Tax mutant selectively deficient in the ability to activate transcription through CREB/ATF demonstrated no detectable changes in morphology or growth characteristics. These results suggest that transcriptional activation through the CREB/ATF pathway may play an important role in Tax-mediated cellular transformation.

Protein extravasation and airway conductance (SGaw) were examined in awake guinea pigs exposed to inhaled endotoxin or saline for three hours. A significant increase in protein extravasation (as estimated by the leakage of protein bound Evans blue dye) was seen in the conducting airways of endotoxin exposed animals compared with saline exposed animals. Mean dye extravasation was significantly increased by one to threefold in the mainstem and hilar bronchi of endotoxin exposed animals. These changes in extravasation were accompanied by decrements in pulmonary function and by an influx of polymorphonuclear leucocytes into the airway wall. The SGaw decreased significantly by 60-90 minutes into exposure to endotoxin and had decreased by 22% and 34% at the end of exposure in the low and high dose endotoxin groups, respectively. Similar findings were obtained in animals exposed to cotton dust. Contrary to studies suggesting that platelet activating factor (PAF) is involved in the systemic and peripheral lung effects of endotoxin, pretreatment with the PAF antagonist WEB2086 did not prevent the conducting airway injury produced by inhaled endotoxin.

Exercise testing early after myocardial infarction has been shown to be of further risk stratification value among otherwise low-risk patients on the basis of an uncomplicated clinical course. The addition of cardiac imaging modalities to exercise testing has augmented this capacity. Exercise echocardiographic imaging before and immediately after treadmill exercise can be accomplished in 85-95% of patients. New or worsening wall motion abnormalities identify 63-80% of patients who will suffer cardiac events and correctly predict 78-95% of those who will not. In addition, exercise echocardiography can detect multivessel coronary artery disease with a sensitivity of 80% and a specificity of 90%. These results are superior to those obtained by analyzing global left ventricular function during exercise, exercise aortic Doppler velocity profiles, or exercise electrocardiography. How exercise echocardiography compares with 201Tl perfusion imaging after myocardial infarction awaits a systematic study. Therefore, the choice between exercise echocardiography and perfusion imaging depends on physician preference, availability, cost, and service.

Noninvasive tests have greatly improved in their ability to diagnose coronary artery disease. In addition, new testing modalities have been added to our armamentarium. However, no test is clearly superior to all others in every clinical circumstance. Moreover, none have been shown to provide sensitivities and specificities consistently above 90%. Therefore, their use for diagnostic purposes in populations with a lower prevalence of disease is only of moderate value. Conversely, for the assessment of the functional significance of coronary artery disease or prognosis in patients with ischemic heart disease, the addition of noninvasive imaging modalities to exercise testing is of high value.

Fibronectin is a multifunctional protein that is synthesized in several different forms that result from alternative splicing of mRNA. Although expression of splicing variants appears to be both developmentally regulated and tissue-specific, the functional significance of these isoforms is largely unknown. We found that cultured airway epithelial cells vectorially secrete two distinct species of fibronectin, one which contains the alternatively spliced EIIIA region (EIIIA+) and one in which the EIIIA segment is spliced out (EIIIA-). Fibronectin containing the EIIIA region is preferentially secreted apically. Although both apical and basal stimulation with transforming growth factor beta 1 increased fibronectin synthesis, the secretory response differed depending on which surface was being stimulated. Apical secretion of fibronectin and expression of EIIIA+ fibronectin mRNA increased only after apical stimulation. These data demonstrate a novel mechanism for the polarized regulation of targeted secretion and alternative splicing of fibronectin and suggest that the EIIIA segment may act as a targeting signal for the vectorial secretion of fibronectin.

OBJECTIVE

To propose a new classification for the primary immunodeficiency disorders and to review potential therapeutic applications of biologic response modifiers in these disorders.

DATA SOURCE

Relevant articles were identified through a search of MEDLINE using the following indexing terms: primary immunodeficiencies (and subclassifications), and human immunomodulators (and subclassifications).

STUDY SELECTION

Articles were critically reviewed and included if relevant.

DATA SYNTHESIS

The primary immunodeficiency disorders are classified according to functional abnormalities, specifically, abnormalities in early cellular maturation, differentiation, regulatory cell function, enzymatic function, and cytokine responses. Such a classification clarifies the potential role of biologic response modifiers in primary immunodeficiency disorders. Intravenous gammaglobulin and histamine-2 (H2)-receptor blockers modify regulatory cell function; retinoids modify abnormal cellular differentiation, gene transfer and enzyme replacement can be applied in disorders characterized by specific functional gene abnormalities; and interferons modify abnormal cytokine responses. Interleukin-2, thymic hormones, transfer factor, and levamisole appear to affect multiple functional defects.

CONCLUSIONS

Biologic response modifiers are currently important ancillary tools in the treatment of immunodeficiency disorders, and their therapeutic role will become even more important in the future. Multi-center cooperative trials of new and existing agents are needed to fully define their roles and efficacy in the treatment of these disorders.

The expression of interleukin (IL) 2, IL-4, IL-10, and interferon gamma (IFN-gamma) by lymphocyte subsets was examined during infection of resistant C57BL/6 and susceptible BALB/c mice with the protozoan parasite Leishmania major. CD4+ and CD8+ T lymphocytes and B lymphocytes were isolated from the lymph nodes draining infectious lesions, and their RNA was examined for lymphokine transcripts. Distinct patterns of CD4+ cell cytokine expression were apparent: C57BL/6 CD4+ cells contained IFN-gamma and IL-2 mRNA, whereas BALB/c CD4+ cells expressed IL-4 and IL-10 message. CD8+ cells contributed little lymphokine expression during disease, but B cells were a major source of IL-2 mRNA in both strains of mice. BALB/c mice made resistant by treatment with anti-CD4 antibody at the time of infection repopulated lymph nodes with CD4+ cells that expressed IL-2 and IFN-gamma. Protective treatment with anti-IL-4 antibody in vivo also resulted in the appearance of CD4+ cells with increased IFN-gamma and diminished IL-4 and IL-10 expression. These data establish CD4+ cells as the primary source of IFN-gamma in healing mice and of IL-4 and IL-10 during progressive infection and confirm that the spectral extremes of this disease are characterized by the presence of CD4+ cells expressing Th1 or Th2 phenotypes in vivo.