Donor MHC-speciﬁc thymus vaccination allows for immunocompatible allotransplantation

Cell Research, 2025 · DOI: https://doi.org/10.1038/s41422-024-01049-5 · Published: January 3, 2025

Simple Explanation

Organ transplantation faces challenges due to MHC mismatch, leading to rejection. This study introduces a "donor MHC-specific thymus vaccination" (DMTV) strategy. DMTV involves expressing donor MHC molecules in the recipient's thymus, causing T cells that recognize these molecules to be depleted, thus inducing tolerance. The study demonstrates successful allotransplantation in mice using DMTV, showing long-term graft tolerance without immunosuppressants.

Study Duration

Not specified

Participants

Mice (C57BL/6, BALB/c, C3H/He, NOD-PrkdcscidIl2rgem1/Smoc (M-NSG))

Evidence Level

Not specified

Key Findings

1
Ectopic expression of allogeneic MHC in the recipient thymus leads to stable expression in TECs and DCs.
2
DMTV results in the specific depletion of donor-reactive T cells, confirmed by MLR analysis and scRNA-seq & scTCR-seq.
3
DMTV mitigates immune rejection of skin allotransplants and allogeneic mouse embryonic stem cell transplants.

Research Summary

The study introduces a donor MHC-specific thymus vaccination (DMTV) strategy to induce T cell tolerance to both autologous and allogeneic donor MHC. DMTV involves expressing allogeneic MHC molecules in the recipient thymus, leading to the depletion of T cells recognizing these molecules and inducing donor-specific immune tolerance. The DMTV strategy demonstrates successful allotransplantation in mice and humanized mouse models, suggesting its potential to overcome the shortage of MHC-matched donor organs.

Practical Implications

Overcoming MHC Matching Dilemma

DMTV could greatly simplify organ allotransplantation by avoiding stringent recipient-donor MHC matching.

Minimizing Immunosuppressant Use

The DMTV strategy has the potential of minimizing the usage of immunosuppressants in the current allotransplantation paradigm.

Expanding Applicability of hESC Therapies

The DMTV strategy might be suitable not only for allogeneic organ transplantation but also for cell-based therapy utilizing products derived from hPSCs.

Study Limitations

1
The potential for AAV infection-induced production of anti-AAV neutralizing antibodies needs to be addressed.
2
The safety and efficacy of DMTV need to be validated in large animal models, such as non-human primates.
3
Banking of AAVs for all HLA-I variants expression is expected to save waiting time for efﬁcient vaccination and transplanta-tion.

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