Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells.

Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-ß1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFß1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the ß7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells.

[Simultaneous kidney and pancreas transplantation (SKPT) in patients with type 1 diabetes and chronic renal failure: experience in 12 patients in Chile]. / Trasplante simultáneo de páncreas y riñon en diabetes mellitus tipo 1: Experiencia de un centro en Chile.

BACKGROUND: Simultaneous kidney and pancreas transplantation (SKPT) is the best alternative for end stage renal disease among patients with insulin dependent diabetes mellitus. AIM: To report our experience with SKPT. MATERIAL AND METHODS: Retrospective analysis of 12 recipients of SKPT transplanted in one center starting in 1994, with a mean follow-up period of 6.8 years (2-15). RESULTS: Eleven of 12 recipients were in chronic hemodialysis before SKPT. Mean A, B, DR and HLA mismatch was 4.3. Mean preformed anti HLA antibodies was 3.3 %. Mean cold ischemia times for pancreas and kidney were 6 and 10 hours, respectively. In the first eight cases, the pancreas was drained to the bladder, and in the last four, an enteric drainage was performed. Eleven recipients were induced with antibodies, and maintenance immunosuppression consisted of cyclosporin or tacrolimus plus an antiproliferative agent. Ten year patient survival was 70%. Pancreas and kidney survival, defined by insulin and dialysis independence, were 72 and 73% respectively. Fifty percent of recipients experienced acute graft rejection (cellular or humoral), with good response to treatment except in one case. CONCLUSIONS: This experience shows that SKPT is associated with an excellent patient survival associated to insulin and dialysis independence in 70% of patients at 10 years.

Trasplante simultáneo de páncreas y riñon en diabetes mellitus tipo 1: Experiencia de un centro en Chile / Simultaneous kidney and pancreas transplantation (SKPT) in patients with type 1 diabetes and chronic renal failure: Experience in 12 patients in Chile

Background: Simultaneous kidney and páncreas transplantation (SKPT) is the best alternative for end stage renal disease among patients with insulin dependent diabetes mellitus. Aim: To report our experience with SKPT. Material andMethods: Retrospective analysis ofl2 recipients of SKPT transplanted in one center starting in 1994, with a meanfollow-upperiod of6.8years (2-15). Results: Eleven ofl2 recipients were in chronic hemodialysis before SKPT. Mean A, B, DR and HLA mismatch was 4.3. Mean preformed anti HLA antibodies was 3.3 percent. Mean cold ischemia times for páncreas and kidney were 6 and 10 hours, respectively. In the first eight cases, the páncreas was drained to the bladder, and in the last four, an enteric drainage was performed. Eleven recipients were induced with antibodies, and maintenance immunosuppression consisted ofCyclosporine or Tacrolimusplus an antiproliferative agent. Ten year patient survival was 70 percent. Páncreas and kidney survival, defined by insulin and dialysis independence, were 72 and 73 percent respectively. Fifty percent of recipients experienced acute graft rejection (cellular or humoral), with good response to treatment except in one case. Conclusions: This experience shows that SKPT is associated with an excellent patient survival associated to insulin and dialysis independence in 70 percent of patients at 10 years.

Autoanticuerpos anticitoplasma de neutrófilos / Neutrophil anticytoplasma autoantibodies

Los ANCA son anticuerpos detectados frecuentemente en enfermedades autoinmunes, especialmente vasculitis. Su actividad se dirige contra diferentes estructuras citoplasmáticas de los neutrófilos. El presente artículo es una revisión de sus especificidades antigénicas, sus métodos de detección, sus correlaciones clínicas y su posible rol etiopatogénico en estas enfermedades