Fully MHC-Disparate Mixed Hemopoietic Chimeras Show Specific Defects in the Control of Chronic Viral Infections

Abstract

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.

Transplantation tolerance and its outcome during infections and inflammation

“…Nevertheless, subtle immune defects can be observed for fully MHC-disparate mixed hematopoietic chimeras during persistent or chronic viral infections, because of ineffective priming of effector cells leading to a reduced ability to clear infected donor cells (Fig. 1), which could be partially alleviated by T-cell adoptive therapy or selected MHC haplotype matching (12, 13). …”

“…1). This immunodeficiency could be partially alleviated by T-cell adoptive therapy or selected MHC haplotype matching (12,13).…”

Hematopoietic Cell Transplantation for Tolerance Induction: Animal Models to Clinical Trials

“…However, the exquisite host restriction of virus-specific CTLs in mixed chimeras (72,73) can allow the persistence of a pathogenic viral reservoir in donor cells if the donor and recipient are fully MHC-mismatched. This problem can be avoided by partial MHC sharing between the donor and recipient (73). …”

Outstanding questions in transplantation: Tolerance

“…Much like combination drug therapy has revolutionized short-term outcomes for standard-of-care transplant recipients, the recipe for successful establishment of stable, IS-independent mixed chimerism may mandate multiple cellular therapeutics.Donor-specific tolerance, if associated with profound off-target immune defects in the transplant recipient, would be an unacceptable outcome. Although small animal studies have highlighted immune defects in MHC-mismatched full donor chimeras,63 in actual clinical practice such defects have not been observed. Published data from the FCRx trial have shown evidence of robust immune reconstitution in all lymphocyte subpopulations and diverse TCR repertoire development in fully chimeric subjects 64.…”