A new compound with an immunosuppressive property was purified from culture filtrates of Isaria sinclairii and was chemically modified to FTY720. Rat spleen cells incubated with FTY720 demonstrated features characteristic of apoptosis--such as the absence of surface microvilli, chromatin condensation, and the formation of apoptotic bodies--by electron microscopy, and genemic DNA fragmentation by agarose gel electrophoresis. When FTY720 was administered in liver-allografted rats at a dose of 0.5 mg/kg from day 1 to day 14 after transplantation, the recipients survived significantly longer than the control group. Pretransplant treatment with 5 mg/kg of FTY720 one day before and on the day of grafting induced a remarkable prolongation of recipient survival, and three of 10 recipients survived for longer than 50 days. Furthermore, administration of FTY720 at 5 mg/kg on days 3 and day 4 after grafting also prolonged survival. In canine kidney allografting, a pretransplant 2-day course of FTY720 at 5 mg/kg prolonged graft survival. Daily administration of FTY720 in combination with CsA resulted in a significant prolongation of graft survival in a synergistic manner. In addition, FTY720 appeared to be nontoxic in canine recipients. These results demonstrated that FTY720, having a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation.
The etiology and pathogenesis of Kawasaki disease (KD) remain unknown. As previously reported, in US patients with acute KD, IgA plasma cells (PCs) infiltrate the vascular wall. To determine whether IgA PCs are increased at mucosal sites in KD and to determine whether other nonvascular KD tissues are infiltrated by IgA PCs, the cells were immunolocalized and quantitated in tissue sections taken from 18 US and Japanese patients who died of acute KD and from 10 age-matched controls. IgA PCs were significantly increased in the trachea of patients who died of acute KD, compared with controls (P<.01), a finding that was similar to findings in children with fatal respiratory viral infection. IgA PCs also infiltrated coronary artery, pancreas, and kidney in all KD patients. These findings strongly support entry of the KD etiologic agent through the upper respiratory tract, resulting in an IgA immune response, with systemic spread to vascular tissue, pancreas, and kidney.
These results suggest that neutrophils are involved in the damage occurring to coronary arteries in the early stage of KD. Vasodilation might occur as a result of injury to vascular walls caused by neutrophils, as well as macrophages.
Kawasaki disease (KD, or acute febrile mucocutaneous lymph node syndrome (MCLS)) was first described as a clinical entity in 1967 by Dr. Tomisaku Kawasaki of the Japan Red Cross Medical Center. Originally, it was thought to have a favorable prognosis, but as epidemiological surveys, augmented by pathological studies, have shown, it has come to be recognized as an often fatal disorder. In this report, the clinical symptoms, historical background, present status of research and epidemiological problems of KD are first described, and then we present a pathological and morphological outline of KD, focusing on pathological changes in the blood vessels, and the relationships of these changes to 1) the morphogenesis of arteritis, 2) the mechanism of coronary artery aneurysm formation and its sequelae, and 3) juvenile arteriosclerosis.
To clarify whether the cardiac sequelae of Kawasaki disease (KD), postcoronary arteritis lesions can become a risk factor for atherosclerosis of the coronary arteries, six autopsy cases of patients older than 15 years of age with coronary arterial lesions caused by arteritis in childhood were examined histologically. Twenty-four arteries were inspected: 10 had no evidence of aneurysm formation, 7 arteries manifested simple dilatation of the lumen, and in 7 arteries there were aneurysms with recanalization. In the group in which there were no aneurysms, "new intimal thickening" was observed in addition to the preexisting intimal thickening which had been caused by arteritis in the acute phase of KD. In the second group with aneurysmal arteries whose lumen remained dilated, thrombotic occlusion occurred in 4 of 6 aneurysms. In addition, advanced atherosclerotic changes (i.e., complicated lesions) were found in a 39-year-old patient. Finally, in the third group of arteries which manifested recanalized lumens after thrombotic occlusion of the aneurysms, new intimal thickening was seen on the internal side and some of them were occluded. The findings in this study suggest that aneurysms present in coronary arteries in individuals with a history of KD constitute a risk factor for atherosclerosis later in life.
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