Abrogating MyD88 Signaling in Donor Lung Resident Hematopoietic Cells Promotes Cell Based Tolerance Induction in Lung Allografts in Mice.

Z. Zheng,¹ J. Wang,¹ X. Yeap,¹ L. Li,³ L. Zhang,² M. He,¹ X. Luo,² Z. Zhang.¹

¹Comprehensive Transplant Center and Department of Surgery, Chicago, IL
²Division of Nephrology and Hypertension, Chicago, IL
³Department of Pathology, Chicago, IL

Meeting: 2017 American Transplant Congress

Abstract number: 395

Keywords: Donors, knockout, Lung transplantation, marginal, Mice, Tolerance

Session Information

Session Name: Concurrent Session: Basic Transplant Tolerance II

Session Type: Concurrent Session

Date: Tuesday, May 2, 2017

Session Time: 2:30pm-4:00pm

Presentation Time: 3:30pm-3:42pm

Location: E350

Objectives: MyD88 signaling plays an important role in allograft rejection and tolerance induction. This study is designed to determine the cellular base of MyD88 expression in donor lung that was crucial in regulating the recruitment of host effectors, additionally; to elucidate roles of donor MyD88 plays in cell based tolerance induction in lung transplant in mice.

Methods: Lungs from wildtype (WT), MyD88 knockout (MyD88^-/-) or chimeric mice on BALB/c background were orthotopically transplanted into untreated B6 mice and B6 treated with ECDI couple donor splenocytes (ECDI-SP) to induce tolerance, respectively. To generate the chimeric mice, bone marrow cells from MyD88^-/-or CD45.1 BALB/c mice were reciprocally injected into irradiated CD45.1 BALB/c or MyD88^-/- mice. Phenotypic analysis of graft infiltrating cells was performed using Flow-Cytometry. Graft function was evaluated by measuring arterial oxygenation (PaO2) and small animal CT. RNAseq examined RNA profiles of sorted graft alveolar macrophage (AM).

Results: Abrogating donor-derived MyD88 signaling significantly decreased infiltration of recipient neutrophils and CD8 T cells into lung allografts in mice on POD 1and POD5. Compared to mice with MyD88 expression restricted to non-hematopoietic parenchymal cells (MyD88^-/-[rArr]WT) group, mice with MyD88 expression restricted to hematopoietic-derived cells (WT[rArr]MyD88^-/-) group restored PaO2 level from 187.5±44.12mmHg to 547.3±32.65mmHg on POD 1. Meanwhile, phenotypic analysis of cellular infiltrates demonstrated there was a significant difference with less neutrophils infiltration in MyD88^-/-[rArr]WT group (p<0.05). Consistently, downregulation of pro-inflammatory cytokines such as TNF, IL-1, IL-6 and chemokines such as macrophage inflammatory protein 2 (MIP-2) was exhibited in the MyD88 deficient donor AM compared to WT donor AM. Furthermore, donor MyD88 deficient lung graft treated with ECDI-SP, a proved tolerance treatment regimen, had decreased inflammation and improved graft function compared to WT with ECDI-SP on POD 14 by CT scan.

Conclusions: Abrogating MyD88 signaling in donor lung resident hematopoietic cells (primary AM) promotes cell based tolerance induction in lung allografts in mice.

CITATION INFORMATION: Zheng Z, Wang J, Yeap X, Li L, Zhang L, He M, Luo X, Zhang Z. Abrogating MyD88 Signaling in Donor Lung Resident Hematopoietic Cells Promotes Cell Based Tolerance Induction in Lung Allografts in Mice. Am J Transplant. 2017;17 (suppl 3).

To cite this abstract in AMA style:

Zheng Z, Wang J, Yeap X, Li L, Zhang L, He M, Luo X, Zhang Z. Abrogating MyD88 Signaling in Donor Lung Resident Hematopoietic Cells Promotes Cell Based Tolerance Induction in Lung Allografts in Mice. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/abrogating-myd88-signaling-in-donor-lung-resident-hematopoietic-cells-promotes-cell-based-tolerance-induction-in-lung-allografts-in-mice/. Accessed May 10, 2025.

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