Pattern of Liver, Kidney, Heart, and Intestine Allograft Rejection in Different Mouse Strain Combinations1

Stomatin-like protein 2 (SLP-2) is a mostly mitochondrial protein that regulates mitochondrial biogenesis and function and modulates T cell activation. To determine the mechanism of action of SLP-2, we generated T cell-specific SLP-2–deficient mice. These mice had normal numbers of thymocytes and T cells in the periphery. However, conventional SLP-2–deficient T cells had a posttranscriptional defect in IL-2 production in response to TCR ligation, and this translated into reduced CD4+ T cell responses. SLP-2 deficiency was associated with impaired cardiolipin compartmentalization in mitochondrial membranes, decreased levels of the NADH dehydrogenase (ubiquinone) iron-sulfur protein 3, NADH dehydrogenase (ubiquinone) 1β subcomplex subunit 8, and NADH dehydrogenase (ubiquinone) 1α subcomplex subunit 9 of respiratory complex I, and decreased activity of this complex as well as of complex II plus III of the respiratory chain. In addition, SLP-2–deficient T cells showed a significant increase in uncoupled mitochondrial respiration and a greater reliance on glycolysis. Based on these results, we propose that SLP-2 organizes the mitochondrial membrane compartmentalization of cardiolipin, which is required for optimal assembly and function of respiratory chain complexes. This function, in T cells, helps to ensure proper metabolic response during activation.

“…Abdominal heterotopic transplants were performed as described (25). After transplant, graft viability was assessed daily by abdominal palpation of the transplant heartbeat.…”

Section: Heart Transplantsmentioning

confidence: 99%

Stomatin-like Protein 2 Deficiency in T Cells Is Associated with Altered Mitochondrial Respiration and Defective CD4+ T Cell Responses

Christie

Mitsopoulos

Blagih

et al. 2012

“…Criteria for rejection included the presence of vasculitis, infarction, lymphocytic infiltration, thrombosis, and hemorrhage. These changes were scored as: 0, no change; 1, minimum change; 2, mild change; 3, moderate change; or 4, marked change (25). Pathology slides were read by a pathologist (B. Garcia) without knowledge of treatment for each case.…”

Section: Histopathological Examinationmentioning

confidence: 99%

Inhibitory Feedback Loop Between Tolerogenic Dendritic Cells and Regulatory T Cells in Transplant Tolerance

Min

Zhou

Ichim

et al. 2003

Self Cite

228

163

An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed important for the induction and maintenance of transplantation tolerance. However, interactions between these cells remain unclear. We induced donor-specific tolerance in a fully MHC-mismatched murine model of cardiac transplantation by simultaneously targeting T cell and DC function using anti-CD45RB mAb and LF 15-0195, a novel analog of the antirejection drug 15-deoxyspergualin, respectively. Increases in splenic Treg and Tol-DC were observed in tolerant recipients as assessed by an increase in CD4+CD25+ T cells and DC with immature phenotype. Both these cell types exerted suppressive effects in MLR. Tol-DC purified from tolerant recipients incubated with naive T cells induced the generation/expansion of CD4+CD25+ Treg. Furthermore, incubation of Treg isolated from tolerant recipients with DC progenitors resulted in the generation of DC with Tol-DC phenotype. Treg and Tol-DC generated in vitro were functional based on their suppressive activity in vitro. These results are consistent with the notion that tolerance induction is associated with a self-maintaining regulatory loop in which Tol-DC induce the generation of Treg from naive T cells and Treg programs the generation of Tol-DC from DC progenitors.

“…This is certainly true for murine skin allografts (1), cardiac allografts (2), intestinal allografts (3), islet allografts (4), and hepatocyte allografts (5). However, it is not necessarily true for liver allografts (3) or renal allografts (6). To date, most experimental effort in transplantation has been directed toward identifying the mechanisms of acute allograft rejection, and its subversion by immunosuppressive agents.…”

mentioning

confidence: 99%

Murine Renal Allografts: Spontaneous Acceptance Is Associated with Regulated T Cell-Mediated Immunity

Bickerstaff¹,

Wang²,

Pelletier³

et al. 2001

It was shown >20 yr ago that mice will spontaneously accept renal allografts in the absence of immunosuppression, but the mechanism responsible for this is not understood. We transplanted DBA/2 (H-2d) kidneys into nephrectomized C57BL/6 (H-2b) mice, and the allografts were spontaneously accepted for >60 days without immunosuppression. In contrast, nonimmunosuppressed cardiac and skin allografts in the same strain combination are rejected within approximately 10 days. The accepted renal allografts have a prominent leukocytic infiltrate, suggesting an ongoing, local immune response. At 60 days post-transplant, the recipients of accepted renal allografts display DBA/2-reactive alloantibodies. They also display DBA/2-reactive delayed-type hypersensitivity responses that are actively counter-regulated by DBA/2-induced TGF-β production, but not by IL-10 production. These data suggest that a donor-reactive, cell-mediated immune mechanism involving TGF-β is associated with the spontaneous acceptance of renal allografts in mice.