Antibody-suppressor CXCR5 + CD8 + T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice.
Jason M ZimmererJing L HanChelsea M PetersonQiang ZengBryce A RingwaldClarissa A CassolSachi R ChaudhariMadison HartJessica HemmingerAnjali A SatoskarMahmoud Abdel-RasoulJiao-Jing WangRobert T WarrenZheng Jenny ZhangChristopher K BreuerGinny L BumgardnerPublished in: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2022)
CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2 b ) were transplanted with A/J kidneys (H-2 a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5 + CD8 + T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5 + CD8 + T cells and CD8-mediated cytotoxicity to alloprimed IgG + B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5 + CD8 + T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG + B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5 + CD8 + T cells (but not alloprimed CXCR5 - CD8 + or third-party primed CXCR5 + CD8 + T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5 + CD8 + T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.
Keyphrases
- cell therapy
- kidney transplantation
- dendritic cells
- regulatory t cells
- cell migration
- lymph node
- peripheral blood
- endothelial cells
- high fat diet induced
- stem cells
- induced apoptosis
- mesenchymal stem cells
- mouse model
- squamous cell carcinoma
- nk cells
- insulin resistance
- immune response
- cell proliferation
- cell death
- cell cycle arrest
- oxidative stress
- adipose tissue