[Knowledge and quality of life in chronic kidney disease and peritoneal dialysis]. / Conocimiento y calidad de vida en enfermedad renal crónica y diálisis peritoneal.

Background: Knowledge of one's own chronic kidney disease (CKD) can improve long-term quality of life (QoL). Peritoneal dialysis presents with residual symptoms that reduce the QoL. Objective: To correlate knowledge of the disease and QoL in patients with CKD and on continuous ambulatory peritoneal dialysis (CAPD). Material and methods: A descriptive, cross-sectional, and prospective study was carried out in patients with CKD treated at a second-level hospital of the Mexican Institute for Social Security (Instituto Mexicano del Seguro Social) in Puebla. SF-36 and KiKS questionnaires were applied. Age, sex, education, marital status, perception of QoL, and level of knowledge were recorded. Descriptive statistics and Spearman's coefficient were used. Results: 199 patients with CKD in CAPD were included, 62.8% women, minimum age range was 18 to 20 years with 4% and maximum of 61 years or more with 49.2%, 35.6% of patients completed primary school, and 65.3% were married. The most frequent comorbidity was diabetes (57.2%). The least affected QoL domain was pain. KiKS recorded a mean of 0.54 (regular knowledge about the disease). It was recorded a weak and significant correlation in the QoL domains: physical health, physical role, pain, general health, mental health (p ≤ 0.05). Conclusions: There is a significant but weak correlation between the perception of QoL and the level of knowledge of the disease in CKD patients with CAPD.

Introducción: el conocimiento adecuado de la enfermedad renal crónica (ERC) puede mejorar la calidad de vida (CV) a largo plazo. La diálisis peritoneal cursa con síntomas residuales que reducen la CV. Objetivo: correlacionar el conocimiento de la enfermedad y la CV en pacientes con ERC y en diálisis peritoneal continua ambulatoria (DPCA). Material y métodos: se llevó a cabo un estudio descriptivo, transversal y prospectivo en pacientes con ERC atendidos en un hospital de segundo nivel de atención del Instituto Mexicano del Seguro Social (IMSS) en Puebla. Se les aplicaron los cuestionarios SF-36 y KiKS. Se registró edad, sexo, escolaridad, estado civil, percepción de calidad de vida, nivel de conocimiento. Se utilizó estadística descriptiva y coeficiente de Spearman. Resultados: se incluyeron 199 pacientes con ERC en DPCA, 62.8% mujeres, edad mínima de 18 a 20 años (4%) y máxima 61 años o más (49.2%), 35.6% de los pacientes cursó primaria completa, y 65.3% estaban casados. La comorbilidad más frecuente fue diabetes (57.2%). El dominio de CV menos afectado fue el dolor. El KiKS registró una media de 0.54 (conocimiento regular sobre la enfermedad). Se registró una correlación débil y significativa en los dominios de CV: salud física, rol físico, dolor, salud general, salud mental (p ≤ 0.05). Conclusiones: existe una correlación significativa pero débil entre la percepción de la CV y el nivel de conocimiento de la enfermedad en los pacientes con ERC con DPCA.

BACH2 in TRegs Limits the Number of Adipose Tissue Regulatory T Cells and Restrains Type 2 Immunity to Fungal Allergens.

FoxP3+ regulatory T cells (Tregs) are essential for self-tolerance and moderating tissue-damaging inflammation. Tregs that develop and mature in the thymus are classified as central Tregs or effector Tregs based on whether Tregs predominately inhabit secondary lymphoid organs (central Tregs) or tissues (effector Tregs). By generating mice that are conditionally deficient for Bach2 in peripheral Tregs, we have examined the role of Bach2 in regulating Treg homeostasis and effector functions. Unlike global and T cell-specific Bach2-deficient mice, Treg-specific Bach2 ablation did not result in unprovoked TH2 inflammation in the lungs. However, Bach2 deficiency in Tregs led to augmented expressions of IRF4, BATF, and GATA3 and a significant increase in the accumulation of ST2 (IL-33R)+ve effector Tregs in the spleen and visceral adipose tissue (VAT) but not in the lungs. Enhanced Bach2-deficient Treg numbers in VAT was not linked to hyperresponsiveness to exogenous IL-33 in vivo. Most strikingly, Treg-specific Bach2 deficiency resulted in enhanced fungal protease-induced Type 2 allergic inflammation in the lungs, with no detectable effects on Type 1 responses to systemic or respiratory viral infections. In summary, we ascribe vital roles for Bach2 in peripheral Tregs: as a transcriptional checkpoint to limit precocious differentiation into effector Tregs in lymphoid tissues and as a regulator of the functional program that restrains Type 2 but not Type 1 inflammation in lungs. Results presented in this manuscript implicate dysregulated Tregs in the pathogenesis of airway hypersensitivities, asthma, and other allergic disorders.

Co-transfer of tumor-specific effector and memory CD8+ T cells enhances the efficacy of adoptive melanoma immunotherapy in a mouse model.

BACKGROUND: Adoptive cell transfer (ACT) is a promising cancer immunotherapeutic strategy that remains ineffective for a large subset of patients. ACT with memory CD8+ T cells (Tmem) has been shown to have superior efficacy compared to traditional ACT with effector CD8+ T cells (Teff). Teff and Tmem have complementary physiological advantages for immunotherapy, but previous publications have not examined ACT using a combination of Teff and Tmem. METHODS: Splenocytes harvested from Ly5.1+/C57BL/6 mice during and after infection with lymphocytic choriomeningitis virus (LCMV) were used to generate bona fide effector and memory CD8+ T cells specific for the LCMV epitope peptide GP33. Congenic Ly5.2+/C57BL/6 mice were inoculated with B16F10 melanoma cells transfected to express very low levels of GP33, then treated with ACT 7 days later with GP33-specific Teff, Tmem, or a combination of Teff + Tmem. RESULTS: Inhibition of melanoma growth was strongest in mice receiving combinatorial ACT. Although combinatorial ACT and memory ACT resulted in maximal intratumoral infiltration of CD8+ T cells, combinatorial ACT induced stronger infiltration of endogenous CD8+ T cells than Tmem ACT and a stronger systemic T cell responsiveness to tumor antigen. In vitro assays revealed rapid but transient melanoma inhibition with Teff and gradual but prolonged melanoma inhibition with Tmem; the addition of Tmem enhanced the ability of Teff to inhibit melanoma in a manner that could be reproduced using conditioned media from activated Tmem and blocked by the addition of anti-IL-2 blocking antibody. CONCLUSIONS: These findings suggest that a novel combinatorial approach that takes advantage of the unique and complementary strengths of tumor-specific Teff and Tmem may be a way to optimize the efficacy of adoptive immunotherapy.

Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice.

Adoptive cell transfer (ACT) melanoma immunotherapy typically employs acutely activated effector CD8+ T cells for their ability to rapidly recognize and clear antigen. We have previously observed that effector CD8+ T cells are highly susceptible to melanoma-induced suppression, whereas memory CD8+ T cells are not. Although memory T cells have been presumed to be potentially advantageous for ACT, the kinetics of local and systemic T cell responses after effector and memory ACT have not been compared. B16F10 melanoma cells stably transfected to express very low levels of the lymphocytic choriomeningitis virus (LCMV) peptide GP33 (B16GP33) were inoculated into syngeneic C57BL/6 mice. Equal numbers of bona fide naïve, effector, or memory phenotype GP33-specific CD8+ T cells were adoptively transferred into mice 1 day after B16GP33 inoculation. The efficacy of ACT immunotherapy was kinetically assessed using serial tumor measurements and flow cytometric analyses of local and systemic CD8+ T cell responses. Control of B16GP33 tumor growth, persistence of adoptively transferred CD8+ cells, intratumoral infiltration of CD8+ T cells, and systemic CD8+ T cell responsiveness to GP33 were strongest after ACT of memory CD8+ T cells. Following surgical tumor resection and melanoma tumor challenge, only mice receiving memory T cell-based ACT immunotherapy exhibited durable tumor-specific immunity. These findings demonstrate how the use of non-expanded memory CD8+ T cells may enhance ACT immunotherapeutic efficacy.

Ctla-4 blockade plus adoptive T-cell transfer promotes optimal melanoma immunity in mice.

Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T-cell populations [eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade-mediated checkpoint inhibition] or introduce exogenously prepared tumor-specific T-cell populations [eg, adoptive cell transfer (ACT)]. Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and nonlymphodepletional ACT could offer additive therapeutic benefit. C57BL/6 mice were inoculated with syngeneic B16F10 melanoma tumors transfected to express low levels of the lymphocytic choriomeningitis virus peptide GP33 (B16GP33), and treated with no immunotherapy, CTLA-4 blockade, ACT, or combination immunotherapy of CTLA-4 blockade with ACT. Combination immunotherapy resulted in optimal control of B16GP33 melanoma tumors. Combination immunotherapy promoted a stronger local immune response reflected by enhanced tumor-infiltrating lymphocyte populations, and a stronger systemic immune responses reflected by more potent tumor antigen-specific T-cell activity in splenocytes. In addition, whereas both CTLA-4 blockade and combination immunotherapy were able to promote long-term immunity against B16GP33 tumors, only combination immunotherapy was capable of promoting immunity against parental B16F10 tumors as well. Our findings suggest that a combinatorial approach using CTLA-4 blockade with nonlymphodepletional ACT may promote additive endogenous and exogenous T-cell activities that enable greater therapeutic efficacy in the treatment of melanoma.