Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States.

We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation.

Purified MHC class I and peptide complexes activate naive CD8+ T cells independently of the CD28/B7 and LFA-1/ICAM-1 costimulatory interactions.

T cells play a central role in the initiation, maintenance, and regulation of the immune response. Effector responses of T cells are controlled by complex combinations of lymphokines and adhesion/costimulatory molecule signals. To isolate the effects of specific adhesion/costimulatory molecules and to define the minimal molecular requirements of naive CD8+ T cell activation, we have developed an APC-free system for stimulation of naive CD8+ T cells. In this report, we demonstrate that immobilized MHC class I-peptide complexes can activate naive CD8+ T cells from TCR transgenic mice at low cell densities. The CD8+ T cells were stimulated to proliferate and secrete IL-2 independently of the molecular interactions between CD28/B7.1-B7.2 or LFA-1/ICAM-1 surface receptors. Previous reports have shown that CD28 ligation is necessary for late T cell survival of APC-stimulated naive CD8+ T cells. Our data suggest that under certain specific conditions of high intensity T cell signaling, early activation and late cell proliferation can occur independently of APC-derived costimulatory signals.

ICAM-1 enhances MHC-peptide activation of CD8(+) T cells without an organized immunological synapse.

In addition to the TCR-ligand interaction, other receptor-ligand pairs, such as LFA-1 and ICAM-1, play a major role in the activation of T cells. Recent studies of T cell activation suggest a coordinated movement of LFA-1 and ICAM-1 in forming a defined zone in the immunological synapse. It is unclear from these studies whether the organized molecular geometry of the immunological synapse is necessary for ICAM-1 enhancement of T cell activation. In this report, we demonstrate that ICAM-1 can enhance the activation of CD8(+) T cells by MHC-peptide in the absence of an organized immunologic synapse. Therefore, although the molecular organization of the immunologic synapse may amplify stimuli, it is not an absolute requirement for either CD8(+) T cell activation or the ICAM-1 enhancement of TCR activation.

ICAM-1 co-stimulation has differential effects on the activation of CD4+ and CD8+ T cells.

T cells play a central role in the initiation, maintenance and regulation of the immune response. Effector responses of T cells are controlled by complex combinations of lymphokines and adhesion/co-stimulatory molecule signals. To isolate the effects of the adhesion/co-stimulatory molecule ICAM-1, we have stimulated purified murine CD4+ and CD8+ T cells with plate-bound anti-CD3 in the presence or absence of plate-bound soluble ICAM-1. In this report, we demonstrate that the co-immobilization of soluble ICAM-1 and anti-CD3 leads to a much greater increase in IL-2 production by CD8+ T cells than CD4+ T cells. The ICAM-1-induced enhancement we observed has differential sensitivity to LFA-1 blockade, depending on the T cell subsets and cytokine evaluated. These effects may play an important role in the generation and modulation of immune responses.

Resección de colon con invasión mínima: colectomía laparoscópica / Colonic resection with minimal invasive technique: laparoscopic coletomy

El éxito de la aplicación de la cirugia laparoscópica en enfermedades de la vesicula y en la apendicitis aguda, ha estimulado a los investigadores a desarrollar avances tecnológicos en un intento para tratar otro tipo de patologias del tracto digestivo. Despues de adquirir experiencia con diversas formas de laparoscopia, y mientras que se perfeccionaba la cirugia clinica del tracto blliar y del apendice y se adelantaban trabajos controlados en animales de laboratorio, se inició un programa piloto para cirugia laparoscópica del colon. Veinte pacientes con rango de edad entre 43 y 88 años, para una edad promedio de 57 años, se sometieron a resección del colon por laparoscopia. En 9 pacientes se realizó hemicolectomía derecha y en 8, sigmoidectomia. El procedimiento de Hartman (resección antero-inferior), y la resección perineoabdominal, fueron realizadas cada una en 1 paciente. Las indicaciones de la cirugia fueron los adenomas vellosos de gran tamaño o adenocarcinoma del colon, en 12 pacientes; enfermedad diverticular, en 5; endometrioma del sigmoide en 1; volvulus cecal en 1 y enfermedad inflamatoria intestinal en 1. El 80 por ciento de los pacientes toleraron dieta liquida en el primer dia posoperatorio y el 70 por ciento fueron dados de alta a las 96 horas con dieta corriente y deposición normal. Se presentaron tres complicaciones quirurgicas: 1) Un paciente presento sangrado posoperatorio que requirió 3 unidades de sangre, tratado sin cirugia. 2) Un paciente desarrolló un edema marcado de la anastomosis rectosigmoidea que requirió descompresion con sonda rectal. 3) Un paciente con cancer metastasico del colon presentó una obstruccion mecánica del intestino delgado 7 dias despues de la cirugia laparoscopica del colon. Aunque la cirugia laparoscopica esta considerada como un procedimiento en evolucion, se piensa que en el future sera potencialmente popular tanto como la colecistectomia laparoscopica.