Presencia de células B con propiedades regulatorias en ganglios drenantes de un tumor murino

En cáncer, las células B han sido clásicamente asociadas a la presentación antigénica, secreción de anticuerpos y activación de células T. Recientemente se comenzó a investigar un posible rol negativo de los linfocitos B sobre la respuesta inmune antitumoral, debido a que se describieron ciertas subpoblaciones B con capacidad de afectar negativamente la respuesta inmune en enfermedades autoinmunes. El tumor murino MCC es altamente inmunogénico en estadios tempranos; a medida que crece pierde su inmunogenicidad e induce inmunosupresión sistémica y tolerancia. En este modelo hemos demostrado previamente que el crecimiento tumoral induce un marcado y progresivo aumento en el número y proporción de células B en los ganglios drenantes del tumor (TDLN) y un aumento menos marcado de células T regulatorias. El objetivo fue estudiar las características y función de las células B en los ganglios que drenan el tumor MCC y analizar si éstas podrían inhibir la respuesta contra el tumor favoreciendo su progresión. Encontramos que las células B en los TDLN presentan expresión aumentada de las moléculas CD86 y MHCII indicando su activación, y expresión intracelular de IL-10, FASL y Granzima B, moléculas con función inmunosupresora. Además, mostraron alta actividad inhibitoria de la proliferación T ex vivo y moderada secreción de anticuerpos. Los resultados indican que aun cuando persisten marcadores de activación de la respuesta inmune, las células B presentes en los ganglios drenantes del tumor muestran fenotipo regulatorio y actividad inhibitoria, sugiriendo que las mismas contribuirían al estado de tolerancia inmunológica característico del estadio de tumor avanzado.In cancer, B cells have been classically associated with antibody secretion, antigen presentation and T cell activation. However, a possible role for B lymphocytes in impairing antitumor response and collaborating with tumor growth has been brought into focus. Recent reports have described the capacity of B cells to negatively affect immune responses in autoimmune diseases. The highly immunogenic mouse tumor MCC loses its immunogenicity and induces systemic immune suppression and tolerance as it grows. We have previously demonstrated that MCC growth induces a distinct and progressive increase in B cell number and proportion in the tumor draining lymph nodes (TDLN), as well as a less prominent increase in T regulatory cells. The aim of this research was to study B cell characteristics and function in the lymph node draining MCC tumor and to analyze whether these cells may be playing a role in suppressing antitumor response and favoring tumor progression. Results indicate that B cells from TDLN expressed increased CD86 and MHCII co-stimulatory molecules indicating activated phenotype, as well as intracellular IL-10, FASL and Granzyme B, molecules with regulatory immunosuppressive properties. Additionally, B cells showed high inhibitory upon T cell proliferation ex vivo, and a mild capacity to secrete antibodies. Our conclusion is that even when evidence of B cell-mediated activity of the immune response is present, B cells from TDLN exhibit regulatory phenotype and inhibitory activity, probably contributing to the state of immunological tolerance characteristic of the advanced tumor condition.Fil: Maglioco, Andrea Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina;Fil: Machuca, Damián Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina;Fil: Camerano, Gabriela Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina;Fil: Costa, Hector Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina;Fil: Ruggiero, Raul Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina;Fil: Dran, Graciela Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina

Compensatory renal growth protects mice against Shiga toxin 2-induced toxicity

Uninephrectomy (Unx) is followed by the compensatory renal growth (CRG) of the remaining kidney. Previous evidence has shown that during CRG, renal tissue is resistant to a variety of pathologies. We tested the hypothesis that the functional changes that take place during CRG could attenuate Shiga toxin (Stx) toxicity in a mouse model of Stx2-induced hemolytic uremic syndrome (HUS). The participation of nitric oxide (NO) was analyzed. After CRG induction with Unx, mice were exposed to a lethal dose of Stx2, and the degree of renal damage and mortality was measured. Stx2 effects on the growth, renal blood flow (RBF) and NO synthase (NOS) intrarenal expression in the remaining kidney were then studied. The induction of CRG strongly prevented Stx2-mediated mortality and renal damage. Administration of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) during CRG partially impaired the protection. Both Stx2 and L-NAME interfered with the hypertrophic and hyperplastic responses to Unx, as well as with the increase in RBF. In intact mice, Stx2 decreased renal perfusion, inhibited endothelial NOS basal expression and enhanced inducible NOS expression; all of these effects were attenuated by prior Unx. It is concluded that during CRG mice are highly protected against Stx2 toxicity and lethality. The protective capacity of CRG could be related to the enhancement of renal perfusion and preservation of eNOS renal expression, counterbalancing two major pathogenic mechanisms of Stx2.Fil: Camerano, Gabriela Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bustuoabad, Oscar David. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Meiss, Roberto Pablo. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Gómez, Sonia Alejandra. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Fernández, Gabriela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Isturiz, Martín Amadeo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Palermo, Marina Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Dran, Graciela Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Methadone as first-line opioid treatment for cancer pain in a developing country palliative care unit

Purpose: The use of methadone for cancer pain is limited by the need of expertise and close titration due to variable half-life. Yet, it is a helpful palliative strategy in low-resources countries given its long-acting effect at low cost and worth additional study. Our aim was to describe the prescription and outcomes of methadone as a first-line treatment for cancer pain in a tertiary palliative care unit (PCU) in Argentina. Methods: Retrospective review of medical records of patients with moderate to severe cancer pain seen at the PCU in 1-year period, who initiated strong opioids at the first consultation. Data collected during the first month of treatment included disease and pain characteristics, initial and final opioid type and dose and need for opioid rotation. Results: Methadone was the most frequent opioid both at the initial and last assessment (71 and 66 % of the prescriptions). In all, treatment with strong opioids provided considerable decrease in pain intensity (p < 0.001) with low and stable opioid dose. Median and interquartile range (IR) of oral morphine equivalent daily dose (OMEDD) was 26 (16–32) and 39 (32–55) mg for initial and final assessments, respectively (p = 0.3). In patients initiated with methadone, the median (IR) daily methadone dose was 5 (4–6) mg at first and 7.5 (6–10) mg at final assessment, and the median (IR) index of opioid escalation was 0 (0–4) mg; (p < 0.05). Patients on methadone underwent less percentage of opioid rotation (15 versus 50 %; p < 0.001) and longer time to rotation (20.6 ± 4.4 versus 9.0 ± 2.7 days; p < 0.001) than patients on other opioids. Conclusions: Results indicate the preference of methadone as first-line strong opioid treatment in a PCU, providing good pain relief at low doses with low need for rotation. Several considerations about the costs of strong opioids in the region are given.Fil: Peirano, Gabriela P.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos Dr. Enrique Tornú; ArgentinaFil: Mammana, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos Dr. Enrique Tornú; ArgentinaFil: Bertolino, Mariela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos Dr. Enrique Tornú; ArgentinaFil: Pastrana, Tania. University of Aachen; AlemaniaFil: Vega, Gloria Fanny. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos Dr. Enrique Tornú; ArgentinaFil: Russo, Jorgelina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos Dr. Enrique Tornú; ArgentinaFil: Varela, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos Dr. Enrique Tornú; ArgentinaFil: Vignaroli, Ernesto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos Dr. Enrique Tornú; ArgentinaFil: Ruggiero, Raul Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Armesto, Arnaldo Raúl. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Camerano, Gabriela Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Dran, Graciela Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

B cells inhibit the antitumor immunity against an established murine fibrosarcoma

Despite the classic role of B cells in favoring the immune response, an inhibitory action of B lymphocytes in tumor immunity has emerged in certain studies. In methylcolanthrene-induced murine fibrosarcoma (MCC), the loss of immunogenicity and the establishment of tolerance are paralleled by systemic immune suppression and the appearance of B+IL‑10+ cells in tumor‑draining lymph nodes. The present study aimed to assess the role of the B+IL‑10+ cell population in the immune evasion and tolerance induced by MCC through the depletion of B cells in mice at various times of tumor progression: Prior to or subsequent to tumor implantation. Tumor growth and immunological parameters were evaluated. B cell depletion prior to tumor inoculum enhanced tumor growth, initiating the onset of the tumor‑induced systemic immune response; however, an increase in the T regulatory cells (Tregs) at the tumor‑draining lymph node could account for tumor exacerbation. B cell depletion once the tumor was established resulted in decreased tumor growth and a delayed onset of tolerance. Additionally, B cell absence exacerbated T cell dependent‑tumor rejection, reduced Tregs and increased cytotoxic CD8+ T cells. In vitro analysis showed a direct effect of B cells upon T cell proliferation. In conclusion, B cell depletion exerts opposite effects when performed prior to or subsequent to tumor implantation. In this initially immunogenic tumor, B cell absence would delay the establishment of immunological tolerance probably by unmasking a pre‑existing antitumor response. The present findings elucidate the convenience of modulating B cells in the development of future and more effective immunotherapies against cancer.Fil: Maglioco, Andrea Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad Abierta Interamericana; ArgentinaFil: Machuca, Damián Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Badano, Maria Noel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Nannini, Paula Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Camerano, Gabriela Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Costa, Hector Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Meiss, Roberto. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Ruggiero, Raul Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Dran, Graciela Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin