Myeloid-derived suppressor cells promote allograft survival by suppressing regulatory T cell dysfunction in high-risk corneal transplantation.

Highly inflamed and neovascularized corneal graft beds are known as high-risk (HR) environments for transplant survival. One of the primary factors leading to this rejection is reduction in the suppressive function of regulatory T cells (Treg). Our results show that myeloid-derived suppressor cells (MDSC) counteract interleukin-6-mediated Treg dysfunction by expressing interleukin-10. Additionally, MDSC maintain forkhead box P3 stability and their ability to suppress IFN-γ+ Th1 cells. Administering MDSC to HR corneal transplant recipients demonstrates prolonged graft survival via promotion of Treg while concurrently suppressing IFN-γ+ Th1 cells. Moreover, MDSC-mediated donor-specific immune tolerance leads to long-term corneal graft survival as evidenced by the higher survival rate or delayed survival of a second-party C57BL/7 (B6) graft compared to those of third-party C3H grafts observed in contralateral low-risk or HR corneal transplantation of BALB/c recipient mice, respectively. Our study provides compelling preliminary evidence demonstrating the effectiveness of MDSC in preventing Treg dysfunction, significantly improving graft survival in HR corneal transplantation, and showing promising potential for immune tolerance induction.

Local administration of myeloid-derived suppressor cells prevents progression of immune-mediated dry eye disease.

Myeloid derived suppressor cells (MDSCs) are a heterogenous population of immature hematopoietic precursors with known immunoregulatory functions. The immunosuppressive role of MDSCs has been highlighted in several inflammatory ophthalmic disorders; however, their therapeutic application in suppressing the immune-mediated changes in dry eye disease (DED) has not been studied. We observed significant reduction in antigen presenting cell (APC) frequencies and their maturation in the presence of MDSCs. Moreover, co-culturing MDSCs with T helper 17 cells (Th17) resulted in reduced Th17 frequencies and their IL-17 expression. On the contrary, MDSCs maintained regulatory T cell frequencies and enhanced their function in-vitro. Furthermore, we delineated the role of interleukin-10 (IL-10) secreted by MDSCs in their immunoregulatory functions. We confirmed these results by flow cytometry analysis and observed that treatment with MDSCs in DED mice effectively suppressed the maturation of APCs, pathogenic Th17 response, and maintained Treg function and significantly ameliorated the disease. The results in this study highlight the potential therapeutic application of MDSCs in treating refractory DED.

IL-6 induces Treg dysfunction in desiccating stress-induced dry eye disease.

Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis, and their dysfunction is implicated in the pathogenesis of various autoimmune disorders, including dry eye disease (DED). Treg dysfunction in DED allows T-helper cell 17 (Th17) mediated chronic inflammation at the ocular surface. In this study, the factors causing Treg dysfunction in DED were investigated. We observed reduced expression of Treg functional markers - FoxP3, CD25, and CTLA-4 in the cells isolated from DED mice (DED Tregs). Additionally, DED Tregs showed increased expression levels of receptors for pro-inflammatory cytokine receptors, namely IL-6R, IL-17RA, and IL-23R. An increased expression level of pro-inflammatory cytokine receptors was observed on exposing Tregs isolated from naïve mice (NTregs) to IL-6 or IL-17, but not IL-23, with a concomitant downregulation of FoxP3, CD25, and CTLA-4 in these cells. Furthermore, among these cytokines, IL-6 induced the most pronounced loss of Treg mediated suppression of Th17 proliferation and IL-10 secretion. In vitro and in vivo blockade of IL-6 effectively restored function in DED Tregs, leading to enhanced suppressive function against proliferating Th17 cells and ameliorating disease severity. In conclusion, this study provides insights into mechanisms of Treg dysregulation in DED, specifically delineating the effect of Th17-associated cytokines, with IL-6 emerging as the critical factor inducing Treg dysfunctionality. These findings highlight the potential for developing novel therapeutic interventions for DED through restoration of immunosuppressive function of Tregs.

Effects of Diabetes Mellitus on Corneal Immune Cell Activation and the Development of Keratopathy.

Diabetes mellitus (DM) is one of the most prevalent diseases globally, and its prevalence is rapidly increasing. Most patients with a long-term history of DM present with some degree of keratopathy (DK). Despite its high incidence, the underlying inflammatory mechanism of DK has not been elucidated yet. For further insights into the underlying immunopathologic processes, we utilized streptozotocin-induced mice to model type 1 DM (T1D) and B6.Cg-Lepob/J mice to model type 2 DM (T2D). We evaluated the animals for the development of clinical manifestations of DK. Four weeks post-induction, the total frequencies of corneal CD45+CD11b+Ly-6G- myeloid cells, with enhanced gene and protein expression levels for the proinflammatory cytokines TNF-α and IL-1ß, were higher in both T1D and T2D animals. Additionally, the frequencies of myeloid cells/mm2 in the sub-basal neural plexus (SBNP) were significantly higher in T1D and T2D compared to non-diabetic mice. DK clinical manifestations were observed four weeks post-induction, including significantly lower tear production, corneal sensitivity, and epitheliopathy. Nerve density in the SBNP and intraepithelial terminal endings per 40x field were lower in both models compared to the normal controls. The findings of this study indicate that DM alters the immune quiescent state of the cornea during disease onset, which may be associated with the progressive development of the clinical manifestations of DK.

Neurokinin-1 Receptor Antagonism Reduces Nonallergic Ocular Redness in a Rabbit Model.

Purpose: To evaluate the therapeutic efficacy of topical application of a neurokinin-1 receptor (NK1R) antagonist in a rabbit model of nonallergic ocular redness. Methods: Nonallergic ocular redness was induced in rabbits by a single, topical application of dapiparzole hydrochloride eye drops (0.5%, 1%, 2%, or 5%). The NK1R antagonist L-703,606 was topically applied to the eye at the same time of induction or 20 min after induction, and phosphate buffered saline (PBS) treatment served as the control. Superior bulbar conjunctival images were taken every 30 s for the first 2 min, followed by every 4 min for 8 min, and then every 10 min until 1 h. The severity of ocular redness was evaluated on the images using ImageJ-based ocular redness index (ORI) calculations. Results: The ORI scores were significantly increased after the application of 0.5%, 1%, 2%, or 5% dapiparzole at each time point evaluated, with the most severe redness induced by the 5% dapiprazole that led to a maximal mean increase in ORI score of 14 at 20 min post-induction and thus used for subsequent evaluation of therapeutic efficacy of NK1R antagonism. Topical L-703,606, when applied at the same time as dapiprazole induction, significantly suppressed the increase of ORI scores at all time points (∼40% decrease). Furthermore, when applied at 20 min after dapiprazole induction, L-703,606 rapidly and effectively suppressed the increase of ORI scores at 30, 40, 50, and 60 min (∼30% decrease). Conclusions: Topical blockade of NK1R effectively prevents and alleviates nonallergic ocular redness in a novel animal model.

Potential applications of mesenchymal stem cells in ocular surface immune-mediated disorders.

We explore the interaction between corneal immunity and mesenchymal stem/stromal cells (MSCs) and their potential in treating corneal and ocular surface disorders. We outline the cornea's immune privilege mechanisms and the immunomodulatory substances involved. In this realm, MSCs are characterized by their immunomodulatory properties and regenerative potential, making them promising for therapeutic application. Therefore, we focus on the role of MSCs in immune-mediated corneal diseases such as dry eye disease, corneal transplantation rejection, limbal stem cell deficiency, and ocular graft-versus-host disease. Preclinical and clinical studies demonstrate MSCs' efficacy in promoting corneal healing and reducing inflammation in these conditions. Overall, we emphasize the potential of MSCs as innovative therapies in ophthalmology, offering promising solutions for managing various ocular surface pathologies.

Effector T Cells Promote Fibrosis in Corneal Transplantation Failure.

Purpose: To evaluate whether fibrosis contributes to corneal transplant failure and to determine whether effector CD4+ T cells, the key immune cells in corneal transplant rejection, play a direct role in fibrosis formation. Methods: Allogeneic corneal transplantation was performed in mice. Graft opacity was evaluated by slit-lamp biomicroscopy, and fibrosis was assessed by in vivo confocal microscopy. Expression of alpha-smooth muscle actin (α-SMA) in both accepted and failed grafts was assessed by real-time PCR and immunohistochemistry. Frequencies of graft-infiltrating CD4+ T cells, neutrophils, and macrophages were assessed using flow cytometry. In vitro, MK/T-1 corneal fibroblasts were co-cultured with activated CD4+CD25- effector T cells isolated from corneal transplant recipient mice, and α-SMA expression was quantified by real-time PCR and ELISA. Neutralizing antibody was used to evaluate the role of interferon gamma (IFN-γ) in promoting α-SMA expression. Results: The majority of failed grafts demonstrated clinical signs of fibrosis which became most evident at week 6 after corneal transplantation. Failed grafts showed higher expression of α-SMA as compared to accepted grafts. Flow cytometry analysis showed a significant increase in CD4+ T cells in failed grafts compared to accepted grafts. Co-culture of activated CD4+CD25- effector T cells with corneal fibroblasts led to an increase in α-SMA expression by fibroblasts. Inhibition of IFN-γ in culture significantly suppressed this increase in α-SMA expression as compared to immunoglobulin G control. Conclusions: Fibrosis contributes to graft opacity in corneal transplant failure and is mediated at least in part by effector CD4+ T cells via IFN-γ.

Morbilidad y mortalidad del distress respiratorio del adulto / Morbidity and mortality of adult respiratory distress

Se estudiaron los 58 pacientes que padecían de distress respiratorio moderado y severo en relación con los agentes causales, en grupos etáreos, hipertensión pulmonar y mortalidad. Se comprueba el 31 de la mortalidad global, sin diferencias significativas entre niños y adultos. La gravedad de la hipertensión pulmonar y del distress respiratorio, de acuerdo con nuestros criterios clínicos, radiológicos, electrocardiográficos y gasométricos resultaron útiles para la clasificación y seguimiento evolutivo de nuestros pacientes. Se revisó la literatura al respecto

Estudio clínico de un grupo de pacientes palúdicos / Clinical study of a group of malarial patients

Se estudiaron 105 pacientes palúdicos ingresados en el ISMM "Luís Díaz Soto", desde enero de 1978, hasta enero de 1984, se destaca como principal manifestación clínica la fiebre. Se realiza un análisis de los elementos clínicos, las complicaciones y los métodos terapéuticos utilizados a la luz de los conocimientos actuales

Pruebas psicológicas y su probable relación con anormalidades electroencefalográficas / Psychological tests and their probable relationship with electroencephalographic abnormalities

Se hizo un estudio en 600 aspirantes a piloto de aviación de transporte examinados en el hospital clinicoquirúrgico "Hnos. Ameijeiras" por la Comisión Central de Medicina Aeronáutica (CCMA) del Instituto de Aviación Civil de Cuba. A todos se les realizó pruebas psicológicas y registros electroencefalográficos con la técnica habitual empleada en la clínica. Se obtuvo una correlación estadísticamente significativa (0,05) entre las alteraciones en el elctroencefalograma y el nivel del cociente de inteligencia, así como con la presencia de elementos de organicidad. Existe una tendencia en los individuos con EEG anormales a tener un nivel de inteligencia promedio o bajo. Es necesario estudios más amplios para lograr llegar a conclusiones más definitivas sobre este aspecto novedoso en la práctica del peritaje médico de vuelo

Hipertensión pulmonar en el síndrome de distress respiratorio del adulto / Pulmonary hypertensión in adult respiratory distress syndrome

Se analizan 58 pacientes que presentan distress respiratorio del adulto moderados y severos de la Clínica de Terapia Intensiva Polivalente del ISMM desde septiembre de 1981 a mayo de 1983. Se evalúa la incidencia e importancia pronóstica de la hipertensión pulmonar en estos pacientes por métodos no cruentos (clínica, radiológica y electrocardiogramas). Se detecta una alta incidencia (82%) de hipertensión pulmonar en el distress respiratorio del adulto, tanto en pacientes adultos como en pediátricos, evidenciándose en relación entre la misma y la sobrevida. Se concluye que estos métodos utilizados son confiables, útiles y de fácil acceso en catástrofes civiles o militares, y pueden ser un criterio fiel de gravedad que se debe utilizar en estas circunstancias

Insuficiencia renal aguda en pacientes quemados / Acute renal failure in burned patients

Se revisan los protocolos de necropsia, los cortes hísticos de riñon y las historias clínicas de 40 pacientes quemados, fallecidos con insuficiencia renal aguda (IRA). Se comprueba la incidencia de IRA en pacientes con más del 20% de la superficie corporal quemada, atribuida a la sepsis, al shock y a la acción de medicamentos nefrotóxicos. Se informa que el distress respiratorio constituyó la principal y más severa complicación, así como la fundamental causa de muerte y se presentó en pacientes que tuvieron diuresis normal o disminuida y un balance hídrico positivo generalmente. Se observan lesiones renales de nefrosis tubular aguda en el 90% de los casos, frecuentemente acompañada de nefrosis hemoglobinúrica y de nefrosis osmótica, congestión vascular glomerular e intersticial. Se insiste en la necesidad de un estudio sistemático de la función renal en todo gran quemado, así como la reposición de volumen en pacientes con diuresis normal o disminuida

Antibióticos y pacientes críticos / Antibiotics and patients under critical conditions

Se analizaron las principales implicaciones, de los antibióticos en el paciente quirúrgico crítico y se hizo énfasis en las contraindicaciones y nuevas modalidades del tratamiento. Se esbozaron los principios generales de los mismos, las normas que rigen su uso, asociaciones y se destacan los conceptos clásicos y modernos en la profilaxis

Definición de la fórmula y la tecnología de un alimento enteral a base de soya: su aplicación / Definition of the formula technology of an enteral food based on soy: its application

Se define la fórmula y la tecnología de unproducto enteral a base de soya a la cual se le realizaron pruebas clínicas y bioquímicas con resultados satisfactorio. Se comparan con otros productos enterales. Se recomienda su uso en pacientes graves hospitalizados