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1.
Am J Physiol Renal Physiol ; 316(5): F957-F965, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30864839

RESUMEN

Ischemia-reperfusion injury represents one of the most common causes of acute kidney injury, a serious and often deadly condition that affects up to 20% of all hospitalized patients in the United States. However, the current standard assay used universally for the diagnosis of acute kidney injury, serum creatinine, does not detect renal damage early in its course. Serendipitously, we found that the immunofluorescent signal of the constitutive podocyte marker podoplanin fades in the glomerulus and intensifies in the tubulointerstitial compartment of the kidney shortly after ischemia-reperfusion injury in 8- to 10-wk-old male C57Bl/6j mice. Therefore, we sought to define the appearance and course of the podoplanin-positive signal in the kidney after ischemia-reperfusion injury. The tubulointerstitial podoplanin-positive signal increased as early as 2 h but persisted for 7 days after ischemia-reperfusion injury. In addition, the strength of this tubulointerstitial signal was directly proportional to the severity of ischemia, and its location shifted from the tubules to interstitial cells over time. Finally, we detected podoplanin in the urine of mice after ischemia, and we observed that an increase in the urine podoplanin-to-creatinine ratio correlated strongly with the onset of renal ischemia-reperfusion injury. Our findings indicate that the measurement of urine podoplanin harbors promising potential for use as a novel biomarker for the early detection of ischemia-reperfusion injury of the kidney.


Asunto(s)
Lesión Renal Aguda/orina , Glicoproteínas de Membrana/orina , Podocitos/metabolismo , Daño por Reperfusión/orina , Lesión Renal Aguda/patología , Animales , Biomarcadores/orina , Creatinina/orina , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Podocitos/patología , Daño por Reperfusión/patología , Índice de Severidad de la Enfermedad , Factores de Tiempo , Regulación hacia Arriba
2.
Transplant Direct ; 6(8): e589, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32766437

RESUMEN

BACKGROUND: Organ transplantation is a standard therapeutic strategy for irreversible organ damage, but the utility of nerve transplantation remains generally unexplored, despite its potential benefit to a large patient population. Here, we aimed to establish a feasible preclinical mouse model for understanding the cellular mechanisms behind the rejection of peripheral and optic nerves. METHODS: We performed syngenic and allogenic transplantation of optic and sciatic nerves in mice by inserting the nerve grafts inside the kidney capsule, and we assessed the allografts for signs of rejection through 14 d following transplantation. Then, we assessed the efficacy of CTLA4 Ig, Rapamycin, and anti-CD3 antibody in suppressing immune cell infiltration of the nerve allografts. RESULTS: By 3 d posttransplantation, both sciatic and optic nerves transplanted from BALB/c mice into C57BL/6J recipients contained immune cell infiltrates, which included more CD11b+ macrophages than CD3+ T cells or B220+ B cells. Ex vivo immunogenicity assays demonstrated that sciatic nerves demonstrated higher alloreactivity in comparison with optic nerves. Interestingly, optic nerves contained higher populations of anti-inflammatory PD-L1+ cells than sciatic nerves. Treatment with anti-CD3 antibody reduced immune cell infiltrates in the optic nerve allograft, but exerted no significant effect in the sciatic nerve allograft. CONCLUSIONS: These findings establish the feasibility of a preclinical allogenic nerve transplantation model and provide the basis for future testing of directed, high-intensity immunosuppression in these mice.

3.
Sci Rep ; 9(1): 6535, 2019 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-31024011

RESUMEN

A primary goal in the management of burn wounds is early wound closure. The use of skin allografts represents a lifesaving strategy for severe burn patients, but their ultimate rejection limits their potential efficacy and utility. IL-6 is a major pleiotropic cytokine which critically links innate and adaptive immune responses. Here, we devised anti-IL-6 receptor eluting gelatin methacryloyl (GelMA) biomaterials (GelMA/anti-IL-6), which were implanted at the interface between the wound beds and skin allografts. Our visible light crosslinked GelMA/anti-IL-6 immunomodulatory biomaterial (IMB) demonstrated a stable kinetic release profile of anti-IL-6. In addition, the incorporation of anti-IL-6 within the GelMA hydrogel had no effect on the mechanical properties of the hydrogels. Using a highly stringent skin transplant model, the GelMA/anti-IL-6 IMB almost doubled the survival of skin allografts. The use of GelMA/anti-IL-6 IMB was far superior to systemic anti-IL-6 receptor treatment in prolonging skin allograft survival. As compared to the untreated control group, skin from the GelMA/anti-IL-6 IMB group contained significantly fewer alloreactive T cells and macrophages. Interestingly, the environmental milieu of the draining lymph nodes (DLNs) of the mice implanted with the GelMA/anti-IL-6 IMB was also considerably less pro-inflammatory. The percentage of CD4+ IFNγ+ cells was much lower in the DLNs of the GelMA/anti-IL-6 IMB group in comparison to the GelMA group. These data highlight the importance of localized immune delivery in prolonging skin allograft survival and its potential utility in treating patients with severe burns.


Asunto(s)
Aloinjertos/efectos de los fármacos , Materiales Biocompatibles/farmacología , Supervivencia de Injerto/efectos de los fármacos , Factores Inmunológicos/farmacología , Interleucina-6/inmunología , Trasplante de Piel , Animales , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Femenino , Fibrosis , Gelatina/química , Supervivencia de Injerto/inmunología , Inflamación/patología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Metacrilatos/química , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Porcinos , Linfocitos T/efectos de los fármacos , Adhesivos Tisulares/farmacología
4.
JCI Insight ; 3(20)2018 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-30333312

RESUMEN

Recent studies in cancer research have focused intensely on the antineoplastic effects of immune checkpoint inhibitors. While the development of these inhibitors has progressed successfully, strategies to further improve their efficacy and reduce their toxicity are still needed. We hypothesized that the delivery of anti-PD-1 antibody encapsulated in PLGA nanoparticles (anti-PD-1 NPs) to the spleen would improve the antitumor effect of this agent. Unexpectedly, we found that mice treated with a high dose of anti-PD-1 NPs exhibited significantly higher mortality compared with those treated with free anti-PD-1 antibody, due to the overactivation of T cells. Administration of anti-PD-1 NPs to splenectomized LT-α-/- mice, which lack both lymph nodes and spleen, resulted in a complete reversal of this increased mortality and revealed the importance of secondary lymphoid tissues in mediating anti-PD-1-associated toxicity. Attenuation of the anti-PD-1 NPs dosage prevented toxicity and significantly improved its antitumor effect in the B16-F10 murine melanoma model. Furthermore, we found that anti-PD-1 NPs undergo internalization by DCs in the spleen, leading to their maturation and the subsequent activation of T cells. Our findings provide important clues that can lead to the development of strategies to enhance the efficacy of immune checkpoint inhibitors.


Asunto(s)
Antineoplásicos Inmunológicos/administración & dosificación , Células Dendríticas/inmunología , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Antineoplásicos Inmunológicos/toxicidad , Línea Celular Tumoral/trasplante , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Linfotoxina-alfa/genética , Ratones , Ratones Noqueados , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/mortalidad , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Receptor de Muerte Celular Programada 1/inmunología , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Resultado del Tratamiento
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