PubMed · 1630952
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J Walker. Taking pains.. https://pubmed.ncbi.nlm.nih.gov/1630952/
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Acute graft-versus-host diseases (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). T helper 1 (Th1)-type cytokines such as interferon-gamma or tumor necrosis factor-alpha have been implicated in the pathogenesis of acute GVHD. TAK-603 is a new quinoline derivative, which is now in clinical trials for use as a disease-modifying antirheumatic drug. In preclinical studies, it inhibited delayed-type hypersensitivity, but not Arthus-type reaction, in mice, and selectively suppressed Th1 cytokine production. Thus, the present study was designed to investigate whether the Th1 inhibitor (TAK-603) ameliorates lethal acute GVHD in a mouse model. Administration of TAK-603 into BALB/c mice given 10 Gy total body irradiation followed by transplantation of bone marrow and spleen cells from C57BL/6 mice markedly reduced the mortality in association with minimal signs of GVHD pathology in the liver, intestine, and skin. TAK-603 reduced not only the production of Th1-type cytokines, but also the proportion of Th1 cells in CD4(+) helper T cells in this GVHD mouse model. These results suggest that TAK-603 could be a potent therapeutic agent for acute lethal GVHD.
Type I diabetes and multiple sclerosis (MS) are distinct autoimmune diseases where T cells target either islet or CNS self-proteins. Unexpectedly, we found that autoreactive T cells in diabetic patients, relatives with high diabetes risk, nonobese diabetic (NOD) mice, and MS patients routinely target classical islet as well as CNS autoantigens. The pathogenic potential of CNS autoreactivity was testable in NOD mice. Pertussis holotoxin, without additional Ags or adjuvants, allowed development of an NOD mouse-specific, autoimmune encephalitis with variable primary-progressive, monophasic, and relapsing-remitting courses. T cells from diabetic donors transferred CNS disease to pertussis toxin-pretreated NOD.scid mice, with accumulation of CD3/IFN-gamma transcripts in the brain. Diabetes and MS appear more closely related than previously perceived. NOD mouse-specific, autoimmune encephalitis provides a new MS model to identify factors that determine alternative disease outcomes in hosts with similar autoreactive T cell repertoires.
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are effective in the secondary prevention of ischemic heart disease, but they do not reduce the rate of restenosis. Vascular ACE activity in the culprit coronary lesions of these patients, however, has never been quantified. METHODS AND RESULTS: We measured the ACE activity of vascular tissue obtained by directional coronary atherectomy in patients with acute coronary syndrome (n=17) and in patients with stable ischemic heart disease (n=36), with and without restenosis. The ACE activity of the culprit coronary lesions was significantly increased in patients with acute coronary syndrome (0.87+/-0.12 nmol. min(-1). mg protein(-1); P:<0.01) but not in patients with ischemic heart disease with restenosis (n=11, 0.19+/-0.05 nmol. min(-1). mg protein(-1)) when compared with those patients with ischemic heart disease without restenosis (n=25, 0.20+/-0.05 nmol. min(-1). mg protein(-1)). There was no difference between the ACE activity of the coronary tissue of the in-stent (n=5) and stent-unrelated (n=6) restenosis patients (0.24+/-0.10 versus 0.15+/-0.04 nmol. min(-1). mg protein(-1)). Serum ACE activity did not differ significantly among the patients. CONCLUSIONS: The present study demonstrates increased ACE activity in culprit lesions in acute coronary syndrome, indicating that enhanced ACE activity is related to the causative mechanism of active coronary lesions.