Fully MHC-disparate mixed hemopoietic chimeras show specific defects in the control of chronic viral infections.
The establishment of mixed allogeneic chimerism can induce donor-specific transplantation tolerance across full MHC barriers. However, a theoretical disadvantage of this approach is the possibility that the state of mixed chimerism might negatively affect the recipient's immune competence to control pathogens. Previous studies using murine models have not supported this hypothesis, because they indicate that acute viral infections are cleared by chimeric animals with similar kinetics to that of unmanipulated controls. However, chronic or persistent viral infections often require a more complex and sustained response with cooperation between CD4 Th cells, CTL, and B cells for effective control. The current study indicates that profound defects become manifest in the control of chronic pathogenic infections in MHC-disparate mixed allogeneic chimeric mice. Furthermore, we show that ineffective priming of the donor-restricted CTL response leads to virus persistence, as well as severe T cell exhaustion. Our results further suggest that either T cell adoptive immunotherapy or selected MHC haplotype matching partially restore immune competence. These approaches may facilitate the translation of mixed chimerism therapeutic regimens.
Emory Transplant Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
Brent H
BH
Koehn
Matthew A
MA
Williams
Keshawna
K
Borom
Shivaprakash
S
Gangappa
Thomas C
TC
Pearson
Rafi
R
Ahmed
Christian P
CP
Larsen
D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D006410:Hematopoiesis / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D018183:Transplantation Chimera / Q000276:immunology* / Q000821:virology; D023001:Transplantation Tolerance / Q000276:immunology; D014184:Transplantation, Homologous
D006649:Histocompatibility Antigens