RESUMO
BACKGROUND: The major histocompatibility complex type II is downregulated in glioblastoma (GB) due to the silencing of the major transcriptional regulator class II transactivator (CIITA). We investigated the pro-immunogenic potential of CIITA overexpression in mouse and human GB. METHODS: The intracerebral growth of wildtype GL261-WT cells was assessed following contralateral injection of GL261-CIITA cells or flank injections with GL261-WT or GL261-CIITA cells. Splenocytes obtained from mice implanted intracerebrally with GL261-WT, GL261-CIITA cells or phosphate buffered saline (PBS) were transferred to other mice and subsequently implanted intracerebrally with GL261-WT. Human GB cells and (syngeneic) GB-infiltrating immune cells were isolated from surgical samples and co-cultured with GB cells expressing CIITA or not, followed by RT-qPCR assessment of the expression of key immune regulators. RESULTS: Intracerebral vaccination of GL261-CIITA significantly reduced the subsequent growth of GL261-WT cells implanted contralaterally. Vaccination with GL261-WT or -CIITA subcutaneously, however, equivalently retarded the intracerebral growth of GL261 cells. Adoptive cell transfer experiments showed a similar antitumor potential of lymphocytes harvested from mice implanted intracerebrally with GL261-WT or -CIITA. Human GB-infiltrating myeloid cells and lymphocytes were not activated when cultured with CIITA-expressing GB cells. Tumor-infiltrating NK cells remained mostly inactivated when in co-culture with GB cells, regardless of CIITA. CONCLUSION: these results question the therapeutic potential of CIITA-mediated immunotherapy in glioblastoma.
RESUMO
Challenging and still unsolved problems in kidney transplantation are risk stratification and the treatment of humoral rejection. Antibody-mediated rejection is an important cause of early and chronic rejection. The impact of donor-specific HLA antibodies on antibody-mediated rejection-causing graft damage is well known, but the clinical relevance of non-HLA antibodies remains unclear. Recently, in 2 independent studies, a new correlation was found between the presence of non-HLA anti-Rho guanosine diphosphate dissociation inhibitor 2 (ARHGDIB) antibodies and increased graft failure. RhoGDI2, another name for ARHGDIB, is a negative regulator of the Rho guanosine triphosphate (RhoGTP)ases RhoA, Rac1m, and Cdc42, whose main function is regulating the actin network in a variety of cells. RhoGDI2 is mainly expressed intracellularly, and some expression is observed on the cell surface. Currently, there is no mechanism known to explain this correlation. Additionally, the reason why the antibodies are produced is unknown. In this review, we will address these questions, provide an overview of other diseases in which these antibodies are prevalent, and describe the physiological role of RhoGDI2 itself. If the mechanism and impact of RhoGDI2 antibodies in kidney graft failure are known, improved risk stratification can be provided to decrease the rate of donor kidney graft failure.