Nobutada Tabata

Role of Natural Killer Cells in Resistance against Friend Retrovirus-Induced Leukemia

ABSTRACT We have previously shown that immunization with a synthetic peptide that contains a single CD4+ T-cell epitope protects mice against immunosuppressive Friend retrovirus infection. Cells producing infectious Friend virus were rapidly eliminated from the spleens of mice that had been immunized with the single-epitope peptide. However, actual effector mechanisms induced through T-helper-cell responses after Friend virus inoculation were unknown. When cytotoxic effector cells detected in the early phase of Friend retrovirus infection were separated based on their expression of cell surface markers, those lacking CD4 and CD8 but expressing natural killer cell markers were found to constitute the majority of effector cells that lysed Friend virus-induced leukemia cells. Depletion of natural killer cells by injecting anti-asialo-ganglio-N-tetraosylceramide antibody did not affect the number of CD4+ or CD8+ T cells in the spleen, virus antigen-specific proliferative responses of CD4+ T cells, or cytotoxic activity against Friend virus-induced leukemia cells exerted by CD8+ effector cells. However, the same treatment markedly reduced the killing activity of CD4− CD8−effector cells and completely abolished the effect of peptide immunization. Although the above enhancement of natural killer cell activity in the early stage of Friend virus infection was also observed in mice given no peptide, these results have demonstrated the importance and requirement of natural killer cells in vaccine-induced resistance against the retroviral infection.

Mycophenolate mofetil therapy for children with intractable nephrotic syndrome.

Background: Cyclosporin A (CyA) can suppress relapses and reduce proteinuria in frequent‐relapse nephrotic syndrome (FRNS) and steroid‐resistant nephrotic syndrome (SRNS). However, some patients remain resistant to CyA therapy. The purpose of the present paper was to evaluate mycophenolate mofetil (MMF) treatment in pediatric patients with CyA‐resistant intractable nephrotic syndrome.

Establishment of Monoclonal Anti-Retroviral gp70 Autoantibodies from MRL/lpr Lupus Mice and Induction of Glomerular gp70 Deposition and Pathology by Transfer into Non-Autoimmune Mice

ABSTRACT Several strains of mice, including MRL/MpJ mice homozygous for the Fas mutant lpr gene (MRL/lpr mice), F1 hybrids of New Zealand Black and New Zealand White mice, and BXSB/MpJ mice carrying a Y-linked autoimmune acceleration gene, spontaneously develop immune complex-mediated glomerulonephritis. The involvement of the envelope glycoprotein gp70 of an endogenous xenotropic virus in the formation of circulating immune complexes and their deposition in the glomerular lesions have been demonstrated, as has the pathogenicity of various antinuclear, antiphospholipid, and rheumatoid factor autoantibodies. In recent genetic linkage studies as well as in a study of cytokine-induced protection against nephritis development, the strongest association of serum levels of gp70–anti-gp70 immune complexes, rather than the levels of antinuclear autoantibodies, with the development and severity of glomerulonephritis has been demonstrated, suggesting a major pathogenic role of anti-gp70 autoantibodies in the lupus-prone mice. However, the pathogenicity of anti-gp70 autoantibodies has not yet been directly tested. To examine if anti-gp70 autoantibodies induce glomerular pathology, we established from unmanipulated MRL/lpr mice hybridoma clones that secrete monoclonal antibodies reactive with endogenous xenotropic viralenv gene products. Upon transplantation, a high proportion of these anti-gp70 antibody-producing hybridoma clones induced in syngeneic non-autoimmune and severe combined immunodeficiency mice proliferative or wire loop-like glomerular lesions. Furthermore, deposition of gp70 in glomeruli and pathological changes were observed after intravenous injection of representative clones of purified anti-gp70 immunoglobulin G, demonstrating pathogenicity of at least some anti-gp70 autoantibodies.

Clinicopathologic features, outcome, and therapeutic interventions in four children with isolated C3 mesangial proliferative glomerulonephritis

Since isolated C3 mesangial proliferative glomerulonephritis in the absence of systemic disease (i-C3-GN) is an uncommon chronic glomerular disease, long-term prognosis and optimal therapeutic intervention for it are not yet fully defined, especially in children. We report clinical features, outcome, and interventions in 4 patients, ranging from 6 to 18 years old, with i-C3-GN. Microscopic or macroscopic hematuria with or without proteinuria was first noted between 3 and 8 years. When present, proteinuria ranged from 0.2 to 1.0xa0g/24xa0h. Persistent hypocomplementemia and circulating immune complexes were found in 1 patient. None of the patients had nephrotic syndrome or hypertension. Percutaneous renal biopsy specimens showed varying degrees of mesangial proliferative glomerulonephritis; 2 patients showed mild mesangial proliferation, while others exhibited moderate histologic severity. In 1 patient with a mild mesangial increase, tubulointerstitial changes were associated. Both patients exhibiting mild mesangial changes followed a benign clinical course with normal renal function over 10 years of follow-up. Patients with moderately severe mesangial alteration manifested slight renal function loss and moderate proteinuria at the time of biopsy, but these largely resolved after a six-month course of prednisolone combined with cyclophosphamide, warfarin, and an angiotensin-converting enzyme inhibitor. Thus, clinical manifestations and the need for aggressive treatment appear to vary among pediatric patients with i-C3-GN. Therapy combining prednisolone with immunosuppression seemed to reduce proteinuria and improve glomerular function in patients with moderately severe mesangial proliferation.

Clinical manifestations and analyses of the cytotoxic T-lymphocyte associated-4 gene in two Japanese families with systemic lupus erythematosus

Although still incompletely understood, the etiology of systemic lupus erythematosus (SLE) is considered to involve both genetic and environmental factors. We encountered two boys with severe SLE from unrelated families and analyzed the gene that encodes cytotoxic T-lymphocyte-associated (CTLA)-4, a protein important in T-cell activation and immune tolerance. Abnormal function of the gene may participate in causation of autoimmune disease, including SLE. In familyxa01, a boy showed serious cardiovascular complications associated with heart failure, and his mother also had clinically active SLE, including nephritis. A boy in familyxa02 developed severe renal complications and peripheral vasculitis accompanied by disseminated petechiae in the lower extremities. His paternal grandfather had died from fibrinous pneumonia caused by SLE. They showed high SLE Disease Activity Index (SLEDAI) score. Analysis of the CTLA-4 gene indicated that the boy in familyxa01 and his mother and the boy in familyxa02 possess a GG genotype in CTLA-4 exonxa01 at +49 together with a 106-bp fragment length of the 3′ untranslated region (UTR) in exonxa04. No association with disease activity was found for polymorphism of the promoter region in exonxa01 at −318 in either family. Disorders of the CTLA-4 gene, especially a GG genotype in exonxa01 at +49 and/or 106-bp fragment length of the 3′UTR in exonxa04, may be involved in early development of SLE in Japanese children, such as the boys described here.

Induction of microthrombotic thrombocytopenia in normal mice by transferring a platelet‐reactive, monoclonal anti‐gp70 autoantibody established from MRL/lpr mice: an autoimmune model of thrombotic thrombocytopenic purpura

MRL/MpJ‐lpr/lpr (MRL/lpr) mice spontaneously develop immune complex‐mediated glomerulonephritis and thrombocytopenia. Although the presence of cross‐reactive anti‐phospholipid antibodies in sera of MRL/lpr mice has been demonstrated, possible relationships between detected autoantibodies and the development of thrombocytopenia have not been elucidated. Recent genetic analyses in a few different strains of lupus‐prone mice have pointed out a close correlation between autoantibodies reactive with endogenous retroviral env gene product, gp70, and the development and severity of glomerulonephritis. In the process of establishing possibly nephritogenic anti‐gp70 autoantibody‐producing hybridoma cells from MRL/lpr mice, we identified an IgG2a‐producing anti‐gp70 hybridoma clone that induced microvascular intraluminal platelet aggregation, thrombocytopenia, and amenia upon transplantation into syngeneic non‐autoimmune mice. This and two other anti‐gp70 antibodies bound onto the surface of mouse platelets, and purified IgG2a of the anti‐gp70 autoantibody induced glomerular lesions with characteristics of thrombotic thrombocytopenic purpura when injected into non‐autoimmune mice. The pathogenic anti‐gp70 autoantibody specifically precipitated a platelet protein with an approximate relative molecular mass of 40u2003000.

A boy undergoing maintenance hemodialysis who developed mediastinal lymph node tuberculosis.

The incidence of tuberculosis (TBC) in patients undergoing maintenance hemodialysis is reported to be higher than that in the general population. We report an 8-year-old boy receiving such treatment for chronic renal failure who developed mediastinal lymph node TBC. He showed only intermittent fever, recurring every 2 weeks, with no other symptoms suggesting TBC. Although staining and culture of pharyngeal swab and gastric juice specimens failed to provide evidence of TBC, a lymph node biopsy specimen disclosed typical pathologic findings of tuberculoma, including caseating granulomas. Antituberculous therapy with isoniazid (INH), rifampicin, pyrazinamide, and ethambutol was given for 12 months, resulting in complete resolution of the TBC, with no subsequent recurrence. To our knowledge, mediastinal lymph node localization of TBC is relatively rare, in a patient on maintenance hemodialysis, especially in a child.

Non-invasive renal artery embolization for renal dysplasia accompanied by hypertension

Renovascular hypertension caused by renal dysplasia often is resistant to drug therapy. For a 14‐year‐old girl with such refractory hypertension, a non‐invasive right renal ablation by embolization with anhydrous ethanol using a shepherd ‘s‐crook’ balloon catheter, was done. Blood pressure then rapidly normalized. Apart from mild fever after the procedure, no adverse effects occurred. In patients with mild renal artery stenosis and hypertension resistant to anti‐hypertensive drug therapy, renal artery embolization may be a useful option.