Pretransplant Infusion of Donor B Cells Enhances Donor-Specific Skin Allograft Survival

Gao, Julia; McIntyre, Megan S. Ford; D'Souza, Cheryl; Zhang, Li

doi:10.1371/journal.pone.0077761

Cited by 4 publications

(2 citation statements)

References 34 publications

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“…The establishment of donor antigen‐specific tolerance has been shown to enhance skin allograft survival, such as pre‐transplant donor B lymphocytes, induced immature dendritic cells, and bioengineering thymus organoids to restore thymus function . Previous studies have showed that ECDI‐SP treatment holds great potential in inducing graft tolerance and prolonging graft survival, including islet, heart, and kidney in mice or rats .…”

Section: Discussionmentioning

confidence: 99%

ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells

Zhou

Zhang

et al. 2019

FASEB BioAdvances

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Rejection is a common complication of allogeneic tissue transplantation. Fixation of splenocytes (SP) with 1‐ethyl‐3‐(3'‐dimethylaminopropyl)‐carbodiimide (ECDI) induces immune tolerance in recipients post‐transplantation; however, the mechanism underlying this effect remains unclear. Here, we determined the mechanisms of ECDI‐fixed donor SP (ECDI‐SP) in inducing tolerance in skin allograft transplantation. C57BL/6‐recipient mice that received Balb/c full‐thickness skin transplants with two infusions of donor‐derived ECDI‐SP, along with rapamycin showed superior skin allograft survival and lower inflammatory cell infiltration than mice that received rapamycin‐only treatment. In ECDI‐SP‐treated mice, the levels of anti‐inflammatory cytokines such as interleukin (IL)‐10 in sera were markedly increased, whereas the expression of inflammatory cytokines was significantly suppressed. Splenic macrophages were significantly polarized to the alternative activated macrophage (M2) phenotype, with expansion of CD4+Foxp3+ regulatory T cells (Tregs) in the spleen and draining lymph nodes. Allostimulatory activity of ECDI‐SP in vitro and donor‐specific ex vivo hyporesponsiveness were observed. C57BL/6 macrophages engulfed allogeneic Balb/c‐derived ECDI‐SP, polarized to the M2 phenotype, with pronounced cAMP response element‐binding (CREB) protein phosphorylation. By facilitating increased IL‐10 expression, ECDI‐SP induced M2 polarization and Treg production, inhibiting effector T‐cell proliferation. Thus, ECDI‐SP modulates macrophage M2 polarization by increasing CREB phosphorylation and promoting Treg production to suppress allogeneic skin graft rejection.

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Section: Discussionmentioning

confidence: 99%

ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells

Zhou

Zhang

et al. 2019

FASEB BioAdvances

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“…Some studies have investigated the subsets of allogeneic donor cells that may be important for inhibiting anti-donor immune responses, but the results remain controversial [ 37 – 42 ]. A previous study demonstrated that a single injection of naïve donor SPL B cells prior to transplantation resulted in significantly prolonged donor-specific skin allograft survival compared to that of the infusion of non-B cells in an MHC class I-mismatched model [ 43 ], indicating the important role of donor B cells in prolonging the survival of donor-specific skin allografts. However, a significant immune-regulatory effects of injection with SPL B cells has not been demonstrated in a MHC class I/II-mismatched model using a fully allogeneic combination.…”

Section: Discussionmentioning

confidence: 99%

PD-L1/PD-L2-expressing B-1 cells inhibit alloreactive T cells in mice

Hirose

Tanaka

et al. 2017

PLoS ONE

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B cells constitute a complex system of antigen-presenting cells (APCs) and exist as distinct subsets that differ in their lineage affiliation, surface molecule expression, and biological function, thus potentially regulating the immune response. In this study, we investigated the immune-regulatory roles of murine B cell subsets as regulatory APCs targeting alloreactive T cells. Either splenic B cells, peritoneal cavity (PerC) B cells, or non-B cells from Balb/c mice were intravenously injected into B6 mice. Serum levels of anti-Balb/c antibodies in the recipients of PerC B cells were significantly lower than those in the recipients of splenic B cells and PerC non-B cells, as determined over a 4-week period after the injection. Mixed-lymphocyte reaction (MLR) assays using splenocytes from the B6 mice at 2 weeks after the injection revealed the significantly reduced anti-Balb/c T cell-responses in the recipients of PerC B cells, as compared to those in the recipients of splenic B cells or untreated control mice. Since PerC B cells contained MHC class II+ CD80+ CD86+ PD-L1+ PD-L2+ cells among the CD5+ B-1a cell subset, PerC B cells from Balb/c mice were pre-incubated with anti-PD-L1/PD-L2 mAbs prior to injection. This treatment abrogated their immune-regulatory effects on anti-Balb/c T cells in the MLR assays. In addition, the inoculation with Balb/c PerC B cells significantly prolonged the survival of subsequently grafted Balb/c hearts in B6 mouse recipients, whereas that with SPL B cells did not. These findings indicate that the PerC B cells, including PD-L1/PD-L2 B-1a cells, may suppress T cells responding to allostimulation, and thus may be optimal for donor lymphocyte injection.

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A disparate subset of double-negative T cells contributes to the outcome of murine fulminant viral hepatitis via effector molecule fibrinogen-like protein 2

Wang

Yan

et al. 2015

Immunol Res

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The underlying immune-mediated mechanisms involved in virus-induced severe hepatitis have not been well elucidated. In this study, we investigated the role of CD3(+)CD4(-)CD8(-) double-negative T (DN T) cells in the pathogenesis of fulminant viral hepatitis (FVH) induced by murine hepatitis virus strain 3 (MHV-3). After MHV-3 infection, the proportions of DN T cells increased significantly in BALB/cJ mice, and splenic DN T cells expressing high levels of CD69 were recruited by MHV-3-infected hepatocytes to the liver. Serum levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin increased, accompanied by massive hepatocyte necrosis. These DN T cells were predominantly consisted of a TCRαβ(+) subset expressing high levels of CD44 and did not produce cytokine except IL-2. Adoptive transfer of this subset of DN T cells to the MHV-3-infected mice resulted in an increase in murine fibrinogen-like protein 2 (mfgl2) expressions in association with massive fibrin deposition in the liver. Following MHV-3 infection, membrane mfgl2 expression and functional procoagulant activity increased remarkably in the DN T cells. Introduction of a recombinant adenovirus which encoded a microRNA specifically targeting mfgl2 gene (Ad-mfgl2-miRNA) in vivo significantly inhibited the hepatic expression of mfgl2 and improved survival in mice. However, under this condition, adoptive transfer of the DN T cells accelerated the disease progression and reversed the benefit from mfgl2 gene silence, leading to a 100 % death rate. Our results demonstrate that DN T cells contribute to the outcome of MHV-3-induced FVH via an important effector molecule mfgl2.

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Pretransplant Infusion of Donor B Cells Enhances Donor-Specific Skin Allograft Survival

Cited by 4 publications

References 34 publications

ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells

ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells

PD-L1/PD-L2-expressing B-1 cells inhibit alloreactive T cells in mice

A disparate subset of double-negative T cells contributes to the outcome of murine fulminant viral hepatitis via effector molecule fibrinogen-like protein 2

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