Acute Rejection Of Human Allografts Research Articles

Landscape of innate immune system transcriptome and acute T cell-mediated rejection of human kidney allografts.

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell-mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.

Interferon-γ converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1.

Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft postcapillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM, but while IFN-γ-activated ECs (γ-ECs) show increased ability to stimulate alloreactive T cells, IFN-γ-activated PCs (γ-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, γ-PCs, ECs, and γ-ECs reveal induction of indoleamine 2,3-dioxygenase 1 (IDO1) in γ-PCs to significantly higher levels than in γ-ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces γ-PC-mediated immunoregulatory effects. Furthermore, human PCs express IDO1 in a skin allograft rejection humanized mouse model and in human renal allografts with acute T cell-mediated rejection. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-γ-induced IDO1-mediated tryptophan depletion.

Production of IL-4 and IL-10 does not lead to immune quiescence in vascularized human organ grafts.

The delineation of T helper cell subsets into T helper type 1 (Th1) and T helper type 2 (Th2) populations based on the production of specific cytokines has been useful in understanding the regulation and progression of immune-based pathologies. In order to test the relevance of this concept to human solid organ transplantation, in situ and system Th1 and Th2 cytokine profiles were characterized in liver allograft recipients. Bile and serum samples obtained posttransplant were analyzed for the cytokines IL-2, IFN-gamma, IL-4, and IL-10. Significant elevations of IL-4 and IL-10 were measured at the site of graft rejection. In contrast, IL-2, IFN-gamma, and IL-4 were markedly elevated in the circulation during rejection. Analyses of sequential bile samples revealed that Th1 and Th2 cytokines showed similar kinetics of production in response to alloantigen. Taken together, these results indicate that acute rejection of human allografts can proceed [correction of procede] in the presence of minimal levels of the Th1 cytokines IL-2 and IFN-gamma and high levels of IL-4 and IL-10.