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Tracking of TCR-Transgenic T Cells Reveals That Multiple Mechanisms Maintain Cardiac Transplant Tolerance in Mice
- Source :
- American Journal of Transplantation. 16:2854-2864
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- Solid organ transplantation tolerance can be achieved following select transient immunosuppressive regimens that result in long-lasting restraint of alloimmunity without affecting responses to other antigens. Transplantation tolerance has been observed in animal models following costimulation or coreceptor blockade therapies, and in a subset of patients through induction protocols that include donor bone marrow transplantation, or following withdrawal of immunosuppression. Previous data from our lab and others have shown that proinflammatory interventions that successfully prevent the induction of transplantation tolerance in mice often fail to break tolerance once it has been stably established. This suggests that established tolerance acquires resilience to proinflammatory insults, and prompted us to investigate the mechanisms that maintain a stable state of robust tolerance. Our results demonstrate that only a triple intervention of depleting CD25+ regulatory T cells (Tregs), blocking programmed death ligand-1 (PD-L1) signals, and transferring low numbers of alloreactive T cells was sufficient to break established tolerance. We infer from these observations that Tregs and PD-1/PD-L1 signals cooperate to preserve a low alloreactive T cell frequency to maintain tolerance. Thus, therapeutic protocols designed to induce multiple parallel mechanisms of peripheral tolerance may be necessary to achieve robust transplantation tolerance capable of maintaining one allograft for life in the clinic.
- Subjects :
- Graft Rejection
0301 basic medicine
Adoptive cell transfer
T cell
medicine.medical_treatment
Receptors, Antigen, T-Cell
Mice, Transgenic
030230 surgery
Lymphocyte Activation
T-Lymphocytes, Regulatory
B7-H1 Antigen
Article
Proinflammatory cytokine
Mice
03 medical and health sciences
0302 clinical medicine
T-Lymphocyte Subsets
Animals
Immunology and Allergy
Medicine
Pharmacology (medical)
IL-2 receptor
Mice, Inbred BALB C
Transplantation
business.industry
Alloimmunity
Peripheral tolerance
Immunosuppression
Allografts
Adoptive Transfer
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Immunology
Heart Transplantation
Transplantation Tolerance
business
Subjects
Details
- ISSN :
- 16006135
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- American Journal of Transplantation
- Accession number :
- edsair.doi.dedup.....d6b073bd6560247643eaadd8d9f8b4d6