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...

An animal model [the nonobese diabetic (NOD) mouse] for type I diabetes features a striking infiltration of T cells into the pancreatic islets. This infiltration selectively destroys beta cells. Most of the T cells are Lyt-l+, but some are Lyt-2+,3+. Transfer experiments using parabiosis revealed that insulitis can be transferred within 2 weeks after parabiosis to immunoincompetent thymectomized mice. When NOD mice (6 mo old) were irradiated and reconstituted with bone marrow cells from young BALB/c nu/nu mice (<2 mo old), the NOD mice exhibited neither insulitis nor overt diabetes. Deposits of immunoglobulin in mesangial areas of the glomeruli disappeared within 3 mo after bone marrow transplantation in such irradiated allogeneic bone marrow reconstituted mice. Assays for immunological functions, including mitogen response and mixed lymphocyte reaction, revealed that both T-and B-cell functions were increased in NOD mice with overt diabetes. NOD mice reconstituted with BALB/c nu/nu bone marrow cells displayed normal T-and B-cell functions. The newly developed T cells in the allogeneic bone marrow recipients are tolerant to cells with both donor-and host-type major histocompatibility complex determinants. These results suggest that bone marrow transplantation may ultimately be developed as a component of a strategy to be employed for treatment of type I diabetes in humans.Diabetes mellitus is a heterogenous disorder, and its pathogenesis remains an enigma. It has been classified into two types (1). Type I is insulin-dependent, often juvenile-onset, nonobese, and ketosis-prone diabetes. Type II is non-insulindependent, adult-onset, obese and non-ketosis-prone diabetes. Animal models of spontaneously developing diabetes mellitus are useful for studying the pathogenesis of human diabetes mellitus and its complications. Many animal models for diabetes mellitus have been reported (2). However, most of them are models for type II diabetes. Only strain BB Wistar rats have been presented as a model for type I diabetes (3). A mouse model for type I diabetes has been sought for some time because mice are well suited for genetic and immunologic analyses.Nonobese diabetic (NOD) mice were found in 1974 by Tochino among Jcl-ICR mice with cataract and have been established recently as an inbred strain by Makino and co-workers (4). Insulitis was observed in more than 90% of both male and female NOD mice at the age of 200 days. The overt diabetic symptoms such as polyuria, polyphagia, hyperglycemia, glycosuria, and ketosis, however, appeared in 90% of the females but only 20% of the males at the age of 250 days (5). In breeding experiments with NOD and C57BL/6J mice, Makino et al. (6) found that insulitis in NOD mice is controlled by two recessive genes on independent chromosomes. Fujita et al. (7) reported that lymphocyte infiltration into the islets selectively destroys beta cells. They also found retrovirus-like particles in pancreatic beta cells of NOD mice (8).We have recently demonstrated that allogeneic bone marr...

Chronic kidney disease of uncertain etiology (CKDu) in North Central Province of Sri Lanka has become a key public health concern in the agricultural sector due to the dramatic rise in its prevalence and mortality among young farmers. Although cadmium has been suspected as a causative pathogen, there have been controversies. To date, the pathological characteristics of the disease have not been reported. Histopathological observations of 64 renal biopsies obtained at Anuradhapura General Hospital from October 2008 to July 2009 were scored according to Banff 97 Working Classification of Renal Allograft pathology. The correlations between the histological observations and clinical parameters were statistically analyzed. Interstitial fibrosis and tubular atrophy with or without nonspecific interstitial mononuclear cell infiltration was the dominant histopathological observation. Glomerular sclerosis, glomerular collapse, and features of vascular pathology such as fibrous intimal thickening and arteriolar hyalinosis were also common. Although hypertension was identified as one of the common clinical features among the cases, it did not influence the histopathological lesions in all the cases. This study concludes that tubulointerstitial damage is the major pathological lesion in CKDu. Exposure(s) to an environmental pathogen(s) should be systematically investigated to elucidate such tubulointerstitial damage in CKDu.

gate the genetic and environmental contributors. We recruited 311 case-series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HbA1c, high serum creatinine or high alpha-1 microglobulin in urine. Results and Discussion: None of 18 metals measured (μg/l) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75−80% of total urinary As was in the form of arsenobetaine, which is non-toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome-wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome-wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; in quantitative trait locus analysis; p=3.73 × 10 −8 in dichotomous analysis) in SLC13A3 (sodium-dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male We conducted a social-environmental-and-genetic epidemiology study on a male population in NCR to investi-

Early diagnosis was the most important factor for improving the prognosis of RPGN patients. To avoid early death due to opportunistic infection in older patients, a milder immunosuppressive treatment such as an initial oral prednisolone dose reduction with or without immunosuppressant is recommended.

To investigate the relationship between high serum levels of IgA and glomerular lesions, selective mating was performed in high serum IgA ddY mice, a murine model of spontaneously developing mesangioproliferative glomerulonephritis mimicking human IgA nephropathy. The selection and mating of high IgA ddY mice were accomplished when the mice were three to four months old. In the 12th generation of high IgA ddY (HIGA) mice, significantly higher levels of serum IgA from 10 age weeks to 60 weeks (P < 0.0002 to 0.0001) were observed in comparison with BALB/c mice. Relatively high proteinuria was observed at 40 weeks of age, although hematuria was consistently negative. Microscopic observations of renal tissue disclosed a marked glomerular mesangial matrix increase and a reduction of cell proliferation with age by both semiquantitative and morphometric analyses with moderate tubulointerstitial damage. These mesangial matrices were stained markedly by antisera for collagen type IV and by fibronectin, but not by collagen type I. Localization of TGF-beta protein was also detected in the mesangium of the HIGA mice. The positive mesangial IgA deposition was maintained consistently by this mating procedure and became more marked with age. Size analysis of IgA from ten pooled HIGA mice aged 50 to 60 weeks revealed dominant polymeric IgA in sera and dimeric IgA in glomerular eluates. Clonal analysis of serum IgA disclosed heterogeneous spectrotypes in a wide pH range (4.5 to 6.5), in contrast to very limited spectrotypes in the acidic pH range (4.5 to 5.2) of IgA in the glomerular eluates from these mice. The analyses of retroviral gp70 antigen involvement in the HIGA mice disclosed a significant increase of serum levels of gp70 anti-gp70 immune complexes with age, with no relationship to the severity of glomerular gp70 deposition. Northern blot analysis of renal tissue revealed markedly high mRNA expression of collagen type I, IV, fibronectin and TGF-beta even in 10-week-old HIGA mice in comparison with BALB/c mice. The expression became more significant in 60-week-old animals. The genetic background required to induce the expansion of IgA-producing B-cell clones is suggested to be closely related to the increased gene expression of TGF-beta, which induces enhanced glomerular extracellular matrix (especially fibronectin) accumulation in HIGA mice, being possibly mediated by the mesangial deposition of dimeric and highly acidic IgA. This newly established strain may provide a model for investigating the relationship between progressive glomerular sclerotic lesions and the induction of pathogenic IgA in human IgA nephropathy.

We identified 27 cases of renal vasculitis (Wegener's granulomatosis 13, microscopic polyangiitis 11, Churg Strauss syndrome 3) fulfilling the case definition. The overall average age was 63.5 years which is less than those of the Japanese patients. The overall annual incidence of renal vasculitis was 12.2/million similar to Japan. The annual incidence of Wegener's granulomatosis was 5.8/million, microscopic polyangiitis 4.9/million and Churg Strauss syndrome 1.4/million. ENT and neurological involvement were much less common in Japan. No patients with cANCA/PR3 were seen in Japan. Wegener's granumolatosis seems to be much less common in Japan than the UK. Discussion. Whilst the overall occurrence of renal vasculitis is similar in Japan to the UK, the clinical phenotype is very different with microscopic polyangiitis predominating in Japan.

In these AAV patients, not only AH but also ILD was frequently observed. AH was associated with the prognosis, but ILD was associated with the long-term prognosis of AAV.