Joäo Américo da Fonseca

Cellular autoreactivity against heat shock protein 60 in renal transplant patients: peripheral and graft-infiltrating responses

Autoreactivity to heat shock protein 60 (Hsp60) has been implicated in the pathogenesis and regulation of chronic inflammation, especially in autoimmune diseases. In transplantation, there is a lack of information regarding the cytokine profile and specificity of cells that recognize self‐Hsp60 as well as the kinetics of autoreactivity following transplantation. We studied the cellular reactivity of peripheral and graft‐infiltrating lymphocytes against Hsp60 in renal transplant patients. Cytokine production induced by this protein in peripheral blood mononuclear cells indicated a predominance of interleukin (IL)‐10 during the late post‐transplantation period, mainly in response to intermediate and C‐terminal peptides. Patients with chronic rejection presented reactivity to Hsp60 with a higher IL‐10/interferon (IFN)‐γ ratio compared to long‐term clinically stable patients. Graft‐infiltrating T cell lines, cocultured with antigen‐presenting cells, preferentially produced IL‐10 after Hsp60 stimulation. These results suggest that, besides its proinflammatory activity, autoreactivity to Hsp60 in transplantation may also have a regulatory role.

Polycythemia after Kidney Transplantation

3 patients with renal transplantation who developed polycythemia presented normalization of the hemoglobin levels immediately after nephrectomy of the native kidneys. This observation induced the authors to study the role of the native kidneys in the genesis of polycythemia in recipients of renal allografts. Comparison was made among 32 patients submitted to renal transplantation, with maintenance of native kidneys (group I) and among 31 under the same conditions, but without the native kidneys (group II). Both groups were comparable according to age, sex, rejection crisis incidence and immunosuppressive therapy. It was observed that the hemoglobin levels of group I were significantly higher (p 59Fe), was higher in patients of group I. The authors concluded that the native kidneys are responsible for the observed polycythemia after a kidney transplantation.

CD4+CD25+Foxp3+ Indirect Alloreactive T cells from Renal Transplant Patients Suppress Both the Direct and Indirect Pathways of Allorecognition

Alloreactive T cells recognize donor antigens by two routes: direct and indirect pathways of allorecognition. Although the direct pathway is reported to be dominant in allograft rejection, indirect allorecognition also plays an important role. Indirect alloreactivity is also observed in renal transplant patients irrespective of rejection. Previously we showed a predominance of interleukin (IL)‐10 induced by indirect allorecognition of donor human leucocyte antigen (HLA)‐DR peptides, suggesting the existence of indirect alloreactive T cells displaying regulatory activity. In the present work, our objective was to characterize these regulatory T cells. We detected indirect alloproliferation of peripheral blood mononuclear cells (PBMC) from renal transplant patients, induced by donor HLA‐DR peptides, dependent on IL‐4 or IL‐10, suggesting regulatory activity as part of the alloreactive T‐cell repertoire. PBMC‐derived indirect alloreactive T‐cell lines were established and produced both inflammatory and regulatory cytokines. We showed that two of these T‐cell lines which were able to inhibit both direct and indirect alloproliferation of another T‐cell line from the same patient presented a CD4+CD25+Foxp3+ T‐cell population. These data support the idea that indirect alloreactive T cells may also have regulatory activity and may contribute to the maintenance of the human renal allograft.

The natural history of diabetic nephropathy in type I diabetes and the role of metabolic control in its prevention, reversibility and clinical course

SummaryThe authors present a contemporary picture of the pathogenesis and clinical course of diabetic nephropathy in type I diabetics describing the stages of the disease and the possible evidence for reversibility of the kidney damage with tight metabolic control. During the socalledlatency period, which is clinically non-detectable, the predominant functional abnormalities (increase in GFR with sub-clinical glomerular proteinuria) can be corrected by strict control although there is no evidence for the regression of the associated anatomical changes such as the enlarged filtration area. As for the described increase in thickness of the glomerular basement membrane, from experimental data and pancreatic transplants in man, delay in its development and to some extent regression of the glomerular lesions can be expected. The problem of how the renal lesions in experimental diabetes mirror the changes in the human kidney is discussed. During thesymptomatic period, with intermittent and subsequently constant proteinuria and progressive decline in renal function, which are observed in only about 30% of type I diabetics, the role of arterial hypertension and its effective control is emphasized. Finally, therenal failure period is indicative of irreversible damage to the kidneys. The progression from its early to its late stages is variable between different patients but each individual patient shows a constant rate of deterioration. The evidence for the efficacy of medical treatment in slowing down its progression is very limited at present but much can be done to improve the quality of life by dietary measures, treatment of fluid overload and hypertension. When the end-stage diabetic kidney disease is reached, with serum creatinine above 8 mg/dl, renal transplantation from a living donor offers a good chance for a relatively acceptable quality of life for years. In conclusion, it is stressed that the morbidity of diabetic nephropathy could eventually be reduced through effective control of the metabolic abnormalities of diabetes with the methods presently available.

Indirect alloreactivity and cytokine production to HLA-DR peptides in human renal transplantation

T HAS BEEN proposed that the indirect pathway of allorecognition to donor major histocompatibility antigens (MHC) plays a significant role in allograft rejection in different animal models and in humans. In human studies, an association between positive proliferative response to donor HLA-DR peptides has been described with both acute and chronic rejection in cardiac transplantation 1,2 as well as in renal 3 and liver 4 chronic rejection. On the other hand, in our previous work we detected in the peripheral blood the indirect alloresponse to a pool of naturally processed alloantigens in a group of long-term renal transplanted patients, irrespective of rejection. 5 In the present study, we evaluated prospectively the indirect alloresponse against HLA-DR allopeptides in renal transplanted patients pretransplantation and in different periods posttransplantation (post-Tx) as well as in normal individuals. To better characterize the T cell repertoires involved in allorecognition, we studied the indirect alloresponse by proliferation and cytokine production.

Contrasting roles of donor and recipient TGFB1 and IFNG gene polymorphic variants in chronic kidney transplant rejection.

OBJECTIVE To assess the long-term impact (minimum of 3 years follow-up) of polymorphisms in cytokine genes in donor:recipient pairs on the results of the transplant. METHODS We compared genetic cytokine polymorphisms and the primary factors of risk for the development of chronic rejection in paired groups of renal transplant patients with and without chronic allograft nephropathy [CAN]. RESULTS Multivariate analysis indicated that the presence of the high-production TT genotype (codon 10) of the transforming growth factor beta-1 (TGFB1) was protective in receptors (p=0.017), contrasting with the increased risk when present in donor samples (p=0.049). On the other hand, in the case of the gamma interferon studied, the greater frequency of the high production allele was protective in the analysis of the donor group (p=0.013), increasing the risk of chronic nephropathy of the allograft when present in the recipients (p=0.036). CONCLUSION Our results highlight the importance of TGFB1 genotyping in donors, and indicate that polymorphisms in the gene of this cytokine in donor cells might contribute to the development of chronic allograft nephropathy.