Terapia Celular Adotiva: O Potencial de Linfócitos B-1 na Modulação da Glicemia e Preservação do Pâncreas Endócrino no Diabetes Experimental

Resumo (EN)

Type 1 Diabetes (T1D) is an autoimmune disease characterized by pancreatic β-cells destruction, resulting in insulin deficiency and impaired glycemic homeostasis. Studies have demonstrated that B-1 lymphocytes play an important immunoregulatory function and may contribute to the prevention of experimental autoimmune diabetes. In this context, the present study aimed to evaluate the effects of the adoptive transfer of metabolically reprogrammed B-1 lymphocytes on glycemic, histopathological, and immunological parameters in XID mice subjected to streptozotocin (STZ)-induced experimental diabetes. Animals were allocated into groups receiving insulin-producing B-1 lymphocytes either at an early stage or after the establishment of STZ-induced diabetes. Body weight, blood glucose progression, intraperitoneal glucose tolerance test (IPGTT), B-1 lymphocyte distribution in different tissues, tracking of transferred cells, pancreatic morphology, and insulin expression within pancreatic islets were evaluated. STZ-induced diabetes promoted persistent hyperglycemia, glucose intolerance, and severe structural alterations in pancreatic islets. Adoptive transfer of metabolically reprogrammed B-1 lymphocytes resulted in heterogeneous responses among treated animals, allowing the identification of responder and non-responder individuals. Responder animals exhibited improved glycemic control and enhanced glucose clearance following glucose challenge. Furthermore, they showed better preservation of pancreatic architecture, with morphologically more organized islets and immunostaining compatible with residual insulin production. In contrast, non-responder animals displayed a profile similar to that of untreated diabetic mice, characterized by persistent hyperglycemia, increased area under the curve (AUC) values during glucose tolerance testing, and greater pancreatic structural impairment, despite the presence of insulin-positive staining within pancreatic tissue. Morphometric analysis of pancreatic islets revealed no statistically significant differences among groups regarding islet area and perimeter, although a trend toward better morphological preservation was observed in some responder animals. Phenotypic analysis demonstrated an increased frequency of B-1 lymphocytes in the peritoneal cavity of treated groups. However, individual analysis revealed the absence of these cells in the peritoneum of responder animals, concomitant with increased frequencies in the liver, a pattern distinct from that observed in non-responders. In the spleen, a significant reduction in this population was observed compared with the STZ group, suggesting a possible modulation of the systemic immune response following adoptive transfer. Morphological evaluation of the inoculum also revealed the emergence of a smaller-sized cell population, occurring at a higher frequency than the lymphocytes typically observed under standard culture conditions. Taken together, these findings demonstrate that the adoptive transfer of metabolically reprogrammed B-1 lymphocytes could promote beneficial effects in a subset of treated animals, contributing to improved glucose tolerance and partial preservation of pancreatic function. However, the variability observed among individuals indicates that therapeutic responsiveness may depend on factors related to the characteristics of the transferred lymphocytes, their migratory capacity and establishment within different organs, as well as host-related factors that remain to be elucidated. These findings highlight the complexity of the mechanisms involved and support the potential of B-1 lymphocytes as a target for innovative therapeutic strategies in T1D.