title: Recipient Myd88 Deficiency Promotes Spontaneous Resolution of Kidney Allograft Rejection.
abstract: The myeloid differentiation protein 88 (MyD88) adapter protein is an important mediator of kidney allograft rejection, yet the precise role of MyD88 signaling in directing the host immune response toward the development of kidney allograft rejection remains unclear. Using a stringent mouse model of allogeneic kidney transplantation, we demonstrated that acute allograft rejection occurred equally in MyD88-sufficient (wild-type [WT]) and MyD88(-/-) recipients. However, MyD88 deficiency resulted in spontaneous diminution of graft infiltrating effector cells, including CD11b(-)Gr-1(+) cells and activated CD8 T cells, as well as subsequent restoration of near-normal renal graft function, leading to long-term kidney allograft acceptance. Compared with T cells from WT recipients, T cells from MyD88(-/-) recipients failed to mount a robust recall response upon donor antigen restimulation in mixed lymphocyte cultures ex vivo. Notably, exogenous IL-6 restored the proliferation rate of T cells, particularly CD8 T cells, from MyD88(-/-) recipients to the proliferation rate of cells from WT recipients. Furthermore, MyD88(-/-) T cells exhibited diminished expression of chemokine receptors, specifically CCR4 and CXCR3, and the impaired ability to accumulate in the kidney allografts despite an otherwise MyD88-sufficient environment. These results provide a mechanism linking the lack of intrinsic MyD88 signaling in T cells to the effective control of the rejection response that results in spontaneous resolution of acute rejection and long-term graft protection.
authors: Division of Nephrology and Hypertension, Department of Medicine.
authors: Nadine M
authors: NM
authors: Lerret
authors: Comprehensive Transplant Center.
authors: Ting
authors: T
authors: Li
authors: Comprehensive Transplant Center.
authors: Jiao-Jing
authors: JJ
authors: Wang
authors: Division of Nephrology and Hypertension, Department of Medicine.
authors: Hee-Kap
authors: HK
authors: Kang
authors: Comprehensive Transplant Center.
authors: Sheng
authors: S
authors: Wang
authors: Comprehensive Transplant Center.
authors: Xueqiong
authors: X
authors: Wang
authors: Comprehensive Transplant Center.
authors: Chunfa
authors: C
authors: Jie
authors: Division of Nephrology and Hypertension, Department of Medicine, Comprehensive Transplant Center, Department of Pathology.
authors: Yashpal S
authors: YS
authors: Kanwar
authors: Comprehensive Transplant Center, Department of Surgery, and Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors: Michael M
authors: MM
authors: Abecassis
authors: Division of Nephrology and Hypertension, Department of Medicine, Comprehensive Transplant Center, Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois zjzhang@northwestern.edu xunrongluo@northwestern.edu.
authors: Xunrong
authors: X
authors: Luo
authors: Comprehensive Transplant Center, Department of Surgery, and zjzhang@northwestern.edu xunrongluo@northwestern.edu.
authors: Zheng
authors: Z
authors: Zhang
mesh_terms: D064591:Allografts; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation; D006084:Graft Rejection; D006085:Graft Survival; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D016030:Kidney Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D000081207:Primary Immunodeficiency Diseases; D054398:Receptors, CCR4 / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D015398:Signal Transduction; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000166:cytology; D014184:Transplantation, Homologous
chemical_list: D039481:CD11b Antigen; C515355:Ccr4 protein, mouse; C515188:Cxcr3 protein, mouse; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; C577686:interleukin-6, mouse
keywords: acute allograft rejection; function; kidney transplantation; lymphocytes; renal; transgenic mouse