Donor CD8+ T cells facilitate induction of chimerism and tolerance without GVHD in autoimmune NOD mice conditioned with anti-CD3 mAb.
Prevention of autoimmune diabetes and induction of islet transplantation tolerance in nonobese diabetic (NOD) mice can be reached by induction of mixed chimerism via bone marrow transplantation (BMT), but this procedure requires total body irradiation (TBI) conditioning of the recipients. The toxicity of radiation and potential for graft-versus-host disease (GVHD) prevents its clinical application. Donor CD8+ T cells play a critical role in facilitation of engraftment but also contribute to induction of GVHD in TBI-conditioned recipients. Here, we showed that high doses of donor CD8+ T cells in combination with bone marrow (BM) cells induced mixed chimerism without GVHD in NOD recipients conditioned with anti-CD3 monoclonal antibody (mAb). The prevention of GVHD in those recipients was associated with low-level production of inflammatory cytokines (ie, tumor necrosis factor alpha [TNF-alpha]), high-level production of anti-inflammatory cytokines (ie, interleukin 4 [IL-4] and IL-10), and confining of the donor CD8+ T-cell expansion to lymphohematopoietic tissues. The chimeric NOD recipients showed donor-specific tolerance and reversal of insulitis. These results demonstrate that donor CD8+ T-cell-mediated facilitation of engraftment can be separated from GVHD in nonirradiated recipients. This regimen may have potential application in the treatment of autoimmune disorders as well as induction of transplantation tolerance.
Liang
Yaming
Y
Department of Diabetes, The Beckman Research Institute, Gonda Building, R2017, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA 91010, USA.
Huang
Tammy
T
Zhang
Chunyan
C
Todorov
Ivan
I
Atkinson
Mark
M
Kandeel
Fouad
F
Forman
Stephen
S
Zeng
Defu
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000379:methods*; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000637:transplantation*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007108:Immune Tolerance; D051379:Mice; D016688:Mice, Inbred NOD; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines