Donor CD8+ T cells mediate graft-versus-leukemia activity without clinical signs of graft-versus-host disease in recipients conditioned with anti-CD3 monoclonal …

C Zhang, J Lou, N Li, I Todorov, CL Lin… - The Journal of …, 2007 - journals.aai.org
C Zhang, J Lou, N Li, I Todorov, CL Lin, YA Cao, CH Contag, F Kandeel, S Forman, D Zeng
The Journal of Immunology, 2007journals.aai.org
Donor CD8+ T cells play a critical role in mediating graft-vs-leukemia (GVL) activity, but also
induce graft-vs-host disease (GVHD) in recipients conditioned with total body irradiation
(TBI). In this study, we report that injections of donor C57BL/6 (H-2 b) or FVB/N (H-2 q) CD8+
T with bone marrow cells induced chimerism and eliminated BCL1 leukemia/lymphoma cells
without clinical signs of GVHD in anti-CD3-conditioned BALB/c (H-2 d) recipients, but
induced lethal GVHD in TBI-conditioned recipients. Using in vivo and ex vivo bioluminescent …
Abstract
Donor CD8+ T cells play a critical role in mediating graft-vs-leukemia (GVL) activity, but also induce graft-vs-host disease (GVHD) in recipients conditioned with total body irradiation (TBI). In this study, we report that injections of donor C57BL/6 (H-2 b) or FVB/N (H-2 q) CD8+ T with bone marrow cells induced chimerism and eliminated BCL1 leukemia/lymphoma cells without clinical signs of GVHD in anti-CD3-conditioned BALB/c (H-2 d) recipients, but induced lethal GVHD in TBI-conditioned recipients. Using in vivo and ex vivo bioluminescent imaging, we observed that donor CD8+ T cells expanded rapidly and infiltrated GVHD target tissues in TBI-conditioned recipients, but donor CD8+ T cell expansion in anti-CD3-conditioned recipients was confined to lymphohematological tissues. This confinement was associated with lack of up-regulated expression of α 4 β 7 integrin and chemokine receptors (ie, CXCR3) on donor CD8+ T cells. In addition, donor CD8+ T cells in anti-CD3-conditioned recipients were rendered unresponsive, anergic, Foxp3+, or type II cytotoxic T phenotype. Those donor CD8+ T cells showed strong suppressive activity in vitro and mediated GVL activity without clinical signs of GVHD in TBI-conditioned secondary recipients. These results indicate that anti-CD3 conditioning separates GVL activity from GVHD via confining donor CD8+ T cell expansion to host lymphohemological tissues as well as tolerizing them in the host.
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