Publications

Leishmania major disseminates in genetically susceptible BALB/c mice to cause fatal disease. Progressive infection has been linked to the failure of parasite-specific Th1, IFN-gamma-producing, CD4+ T lymphocytes to expand and direct macrophage activation and control of intracellular parasitism. In contrast, Th2 CD4+ cell expansion accompanies disease progression. Immunomodulation using CD4 cell depletion at the time of infection results in control of infection and Th1 CD4+ cell expansion. A Th1-like cell line, H1A, was established from the draining lymph nodes of an anti-CD4-pretreated BALB/c mouse infected with L. major, H1A was CD4, TCR(+)-alpha/beta, and released IL-2 and IFN-gamma in response to parasite Ag. A Th2-like cell line, U1A, was established from the lymph node cells of an infected BALB/c mouse that was also CD4, TCR(+)-alpha/beta but released IL-4 and IL-5 after stimulation. Mice with severe combined immunodeficiency were reconstituted with H1A and U1A before infection with L. major. Non-reconstituted mice were unable to restrict parasite growth. Mice reconstituted with H1A healed infection, whereas mice reconstituted with U1A suffered exacerbation of disease. Analysis of spleen cells by flow cytometry confirmed the reconstitution of CD4+ cells in both instances, and stimulation with mitogen established that the lymphokine profile of the donor cells had been maintained during 6 to 8 wk of infection. Histologic analysis of the lesions confirmed migration of donated cells to sites of infection. Neutralization of IFN-gamma in H1A-reconstituted mice and IL-4 in U1A-reconstituted mice reversed the disease phenotype mediated by the two cell lines. These data demonstrate the capacity of CD4+ T cells alone to modulate both positively and negatively the course of leishmaniasis in a lymphokine-dependent manner.

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.