Transplantation of normal bone marrow from C3H/HeN nu/nu (H-2k) mice into young MRL/MPlpr/lpr (MRL/I; H-2k) mice (<1.5 mo) prevented the development of autoimmune diseases and characteristic thymic abnormalities in the recipient mice. When female MRL/1 (>2 mo) or male BXSB (H-2b) mice (9 mo) with autoimmune diseases and lymphadenopathy were lethally irradiated and then reconstituted with allogeneic bone marrow cells from young BALB/c nu/nu (H-2d) mice (<2 mo), the recipients survived for more than 3 mo after the bone marrow transplantation and showed no graft-versus-host reaction. Histopathological study revealed that lymphadenopathy disappeared and that all evidence of autoimmune disease either was prevented from developing or was completely corrected even after its development in such mice. All abnormal T-cell functions were restored to normal. The newly developed T cells were found to be tolerant of both bone marrow donor-type (BALB/c) and host-type (MRL/I or BXSB) major histocompatibility complex (MHC) determinants. Therefore, T-cell dysfunction in autoimmuneprone mice can be associated with both the involutionary changes that occur in the thymus of the autoimmune-prone mice and also to abnormalities that reside in the stem cells.However, normal stem cells from BALB/c nu/nu donors can differentiate into normal functional T cells even in mice whose thymus had undergone considerable involution, as in the case of BXSB or MRL/I mice in the present studies. These findings suggest that marrow transplantation may be a strategy ultimately to be considered as an approach to treatment of lifethreatening autoimmune diseases in humans. T-cell dysfunction in autoimmune-prone mice previously attributed to involutionary changes that occur in the thymus of these mice may instead be attributed to abnormalities that basically reside in the stem cells of the autoimmune-prone mice.The availability of several murine strains that develop systemic lupus erythematosus-like disease has prompted efforts to gain better understanding of the fundamental nature of autoimmune diseases through extensive studies of the immunological abnormalities of these mice. MRL/MP-lpr/lpr (MRL/l) and BXSB mice as well as NZB mice and NZB x NZW F1 hybrids spontaneously develop autoimmune diseases characterized by anti-double-stranded (ds) DNA antibodies, immune-complex glomerulonephritis, and death from renal failure (1). Abnormalities have been found in or attributed to T cells, thymic epithelium, B cells, and/or macrophages in these mice (2-8). Recently, several groups have shown that the proneness to develop autoimmune diseases actually resides in defects at the lymphoid stem-cell level and that defects of function are not directly attributable to environmental factors such as hormones or viruses (9-11).Therefore, we examined whether or not transfer of normal stem cells into autoimmune-prone mice can be used to both prevent and treat autoimmune diseases.In the present study, we show that allogeneic bone marrow transplantation from donors carry...

To clarify the pathophysiologic role of intramyocardial small artery (IMSA) diseases in hypertrophied hearts, narrowings of the IMSA were quantitatively evaluated in 39 autopsied hearts, 10 from patients with typical hypertrophic cardiomyopathy (HCM), four from patients with HCM showing features mimicking dilated cardiomyopathy (DCM-like HCM), 10 from patients with hypertension, and 15 from normal adults. The relations of narrowings of the IMSA to myocytic hypertrophy, myocardial fiber disarray, and fibrosis were also examined. The external caliber and the ratio of the luminal area to the total vascular area (percent luminal area, %lumen) were calculated by an image analyzer in 85 to 203 IMSAs from each patient. The external calibers of the IMSAs were similar among groups of hearts with HCM, hypertensive hearts, and normal hearts but were greater in those with DCM-like HCM. The mean %lumen of the IMSAs was similarly reduced in the hearts with HCM (29 + 5% in the ventricular septum and 31 5% in the left ventricular free wall) and in hypertensive hearts (30 + 8% and 31 + 7%) compared with that in normal hearts (40 5% and 38 + 5%) and was the lowest in the ventricular septum of hearts with DCM-like HCM (17 3%). The mean %lumen of the IMSA was inversely cortelated with heart weight (r = -.59), the mean size of myocytes (r = -.66 in the ventricular septum, r = -.63 in the free wall), and percent fibrotic area in the septum (r = -.68). The mean %lumen values of the IMSAs in the tissues with and without disarray in the hearts with HCM were similar. Thus IMSA disease is of pathophysiologic importance in patients with HCM, DCM-like HCM in particular, or with hypertension. Circulation 75, No. 6, 1130No. 6, -1139No. 6, , 1987 CHEST PAIN is a common symptom of patients with hypertrophic cardiomyopathy (HCM)`2 or systemic hypertension3 despite angiographically normal epicardial coronary arteries. Moreover, these patients often demonstrate abnormal findings on myocardial thallium-201 imaging6 or abnormal lactate metabolism during pacing.7 Pathologically, these hearts show a greater amount of fibrosis distributed predominantly in the subendocardium than in the subepicardium,' and myocardial infarction is sometimes evident.9 Although

SUMMARYThe distribution offibrosis was studied quantitatively in the entire left ventricular wall of a transverse slice of the heart from 10 necropsy cases of hypertrophic cardiomyopathy, 10 cases of hypertensive heart disease, and 20 normal adults. The percentage area (mean (SD)) of fibrosis in the left ventricular wall in hypertrophic cardiomyopathy (10-5 (4-3)%) was significantly greater than that in hypertensive heart disease (2-6 (1-5)%) or in normal hearts (1L1 (0-5)%). In hypertrophic cardiomyopathy the percentage area of fibrosis was greater (13 1 (4-8)%) in the ventricular septum than in the left ventricular free wall (7 7 (4-2)%) whereas in hypertensive heart disease and normal hearts values in these two areas were similar. The percentage area of fibrosis in the left ventricular free wall (where myocardial fibre disarray was not extensive even in hypertrophic cardiomyopathy) was greater in hypertrophic cardiomyopathy than in hypertensive heart disease. The percentage area of fibrosis correlated with heart weight in hypertensive heart disease, but not in hypertrophic cardiomyopathy. These results suggest that widespread fibrosis in hypertrophic cardiomyopathy cannot be explained by cardiac hypertrophy alone, and that disarray and other factors are also important in pathogenesis. The increase in the percentage area of fibrosis from the outer to the inner third of the left ventricular free wall in hypertrophic cardiomyopathy and in hypertension probably reflected transmural gradients of wall stress and myocardial fibre diameter.Although fibrosis is not specific to hypertrophic cardiomyopathy, its quantification and analysis of its regional distribution provide information that is useful in investigating the pathophysiology of the disorder. Patients and methodsForty hearts from necropsy cases were studied-10 with hypertrophic cardiomyopathy, 10 with concentric hypertrophy secondary to hypertension, and 20 normal adult hearts.

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The MRL-lpr/lpr(MRL/l) mouse is a new animal model for human systemic lupus erythematosus (SLE) and skin lesions with hair loss and scab formation are one of the characteristic manifestations in this mouse. We investigated the histopathology of the skin lesions in MRL/l mice and studied the related autoimmune phenomenon. Light microscopical observations revealed hyperkeratosis, acanthosis, hypergranulosis, liquefaction, vasodilation in the dermis and T-cell infiltration into the dermis at the age of 5 months (mo). Immunohistological studies showed the presence of immunoglobulins and/or complement depositions at the dermal-epidermal junction (DEJ). In some mice there was deposition of immunoglobulin at the DEJ at 2 mo and in 90%-100% of MRL/l mice at over 5 mo. Temporal relationship was present among cutaneous immunoglobulin depositions, the occurrence of anti-DNA antibodies and proteinuria. These findings suggest that MRL/l mice might provide a new aid for studying the biological mechanisms of the development of skin lesions in human SLE.