title: Xenoreactive CD4+ memory T cells resist inhibition by anti-CD44 mAb and reject islet grafts via a Th2-dependent pathway.
abstract: BACKGROUND
  Memory T cells are a significant barrier to the induction of transplant tolerance. Our previous study demonstrated that multiple applications of anti-CD44 monoclonal antibody (mAb) could significantly inhibit CD4(+) memory T cells from mediating rejection of cardiac allografts. Now, we sought to explore the effect and mechanism of anti-CD44 mAb on the rejection of islet allografts and xenografts mediated by CD4(+) memory T cells.
  
  
  METHODS
  In this study, we first engrafted skin grafts of C57BL/6 (B6) mice or Dark Agouti (DA) rats onto BALB/c mice to induce donor-reactive memory T cells. We adoptively transferred purified CD4(+) memory T cells to BALB/c origin nude mice and then transplanted islet allografts and xenografts to produce the Allo-Tx and Xeno-Tx models, respectively. We subsequently administered multiple anti-CD44 mAb and observed changes in the survival times of the islet grafts.
  
  
  RESULTS
  In the Allo-Tx model, the mean survival time (MST) of the grafts was 7.7 days in the isotype group, and 20.3 days in the anti-CD44 group. In the Xeno-Tx model, the MST of the grafts was 7.2 days in the isotype group and 8.2 days in the anti-CD44 group. Compared with the isotype group, CD4(+) T cells on the grafts in the anti-CD44 group were significantly decreased in both the Allo-Tx and Xeno-Tx models, but the proportion of CD4(+) memory T cells in the spleens and draining lymph nodes of the recipient nude mice in the anti-CD44 group was significantly decreased in the Allo-Tx model, while it was increased in the Xeno-Tx model. The production of donor-specific IgG antibody in the anti-CD44 group did not vary in the Allo-Tx model, while it was markedly elevated in the Xeno-Tx model. Furthermore, the expression of interferon gamma in the anti-CD44 group was markedly decreased in both the Allo-Tx and Xeno-Tx models, while the expression of IL-4 in the anti-CD44 group was significantly increased only in the Xeno-Tx model.
  
  
  CONCLUSIONS
  Multiple applications of the anti-CD44 mAb could significantly inhibit donor-reactive CD4(+) memory T cells from rejecting grafts via a Th1-dependent pathway, but xenoreactive CD4(+) memory T cells can avoid the effects of anti-CD44 mAb to reject islet xenografts via a Th2-dependent pathway.
authors.affiliation: Organ Transplantation Institute, Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Peng
authors.forename: Jibing
authors.initials: J
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Shao
authors.forename: Feiyu
authors.initials: F
authors.lastname: Wang
authors.forename: Helong
authors.initials: H
authors.lastname: Dai
authors.forename: Panpan
authors.initials: P
authors.lastname: Cheng
authors.forename: Junjie
authors.initials: J
authors.lastname: Xia
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Ruxin
authors.initials: R
authors.lastname: Huang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhu
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Qi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental; D005260:Female; D006085:Graft Survival / Q000276:immunology; D018960:Hyaluronan Receptors / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D051381:Rats; D018418:Th2 Cells / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D018960:Hyaluronan Receptors