The present study strongly suggests that an antibody to TGF-beta is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.

No abstract

Abstract. Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-␤ (TGF-␤) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-␤ and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human anti-TGF-␤ monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-␤ antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-␤ antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition. Diabetic nephropathy, a major long-term complication of diabetes mellitus, is the most common cause of end-stage renal disease requiring dialysis worldwide (1,2) and is becoming a staggering challenge to public healthcare systems due to the prohibitive costs of renal replacement therapy that could become unaffordable even for developed countries. Typical histologic features characterize diabetic nephropathy, including expansion of the extracellular matrix in the glomerular mesangium, thickening of glomerular and tubular membranes, and tubulointerstitial fibrosis, all of them contributing to the inexorable progressive deterioration of renal function (3).Among treatment options for diabetes, agents that inhibit the renin-angiotensin system (RAS) are particularly effective in reducing renal disease progression (4). This is not simply a function of the effect on systemic and glomerular hypertension, but it can be attributed to the unique property of this class of drugs of limiting excess protein ultrafiltration and its deleterious consequences (5). Angiotensin-converting enzyme inhibitor (ACEi) effectiveness, however, depends on timing of treatment. Experimental data in rats with streptozotocin-induced diabete...

Donor treatment with granulocyte-colonystimulating factor (G-CSF) attenuates the ability of donor T cells to induce acute graft-versus-host disease (aGVHD) but increases the severity of chronic GVHD (cGVHD). We investigated the role of the regulatory cytokine transforming growth factor ␤ (TGF-␤) in this paradox in wellestablished murine models of aGVHD and cGVHD wherein recipients undergo transplantation with splenocytes from donors treated with G-CSF. Neutralization of TGF-␤ after stem-cell transplantation (SCT) significantly increased the severity of aGVHD, and the concurrent prevention of interleukin-10 (IL-10) production further exaggerated this effect. Early after SCT, donor T cells were the predominant source of TGF-␤ and were able to attenuate aGVHD in a TGF-␤-dependent fashion. Although the neutralization of TGF-␤ augmented the proliferation and expansion of donor T cells after SCT, it paradoxically impaired cellular cytotoxicity to host antigens and associated graft-versus-leukemia (GVL) effects. In cGVHD, neutralization of TGF-␤ from day 14 after SCT attenuated histologic abnormalities, and CD11b ؉ mononuclear cells infiltrating sclerodermatous skin produced 50-fold more TGF-␤ than corresponding T cells. Thus, though the production of TGF-␤ by donor T cells early after transplantation attenuates aGVHD and is required for optimal GVL, the production of TGF-␤ late after SCT is preferentially from mononuclear cells and mediates cGVHD. These data have important implications for the timing of therapeutic TGF-␤ neutralization to prevent cGVHD after allogeneic SCT.