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Spontaneous restoration of transplantation tolerance after acute rejection.

Miller ML, Daniels MD, Wang T, Chen J, Young J, Xu J, Wang Y, Yin D, Vu V, Husain AN, Alegre ML, Chong AS - Nat Commun (2015)

Bottom Line: Such rejection invariably results in allosensitization and accelerated rejection of secondary donor-matched grafts.When such an allograft is rejected, it has been assumed that the same rules of allosensitization apply as to non-tolerant hosts and that immunological tolerance is permanently lost.Using a mouse model of cardiac transplantation, we show that when Listeria monocytogenes infection precipitates acute rejection, thus abrogating transplantation tolerance, the donor-specific tolerant state re-emerges, allowing spontaneous acceptance of a donor-matched second transplant.

View Article: PubMed Central - PubMed

Affiliation: Section of Rheumatology, Department of Medicine, The University of Chicago, 924 E. 57th Street, JFK-R302, Chicago, Illinois 60637, USA.

ABSTRACT
Transplantation is a cure for end-stage organ failure but, in the absence of pharmacological immunosuppression, allogeneic organs are acutely rejected. Such rejection invariably results in allosensitization and accelerated rejection of secondary donor-matched grafts. Transplantation tolerance can be induced in animals and a subset of humans, and enables long-term acceptance of allografts without maintenance immunosuppression. However, graft rejection can occur long after a state of transplantation tolerance has been acquired. When such an allograft is rejected, it has been assumed that the same rules of allosensitization apply as to non-tolerant hosts and that immunological tolerance is permanently lost. Using a mouse model of cardiac transplantation, we show that when Listeria monocytogenes infection precipitates acute rejection, thus abrogating transplantation tolerance, the donor-specific tolerant state re-emerges, allowing spontaneous acceptance of a donor-matched second transplant. These data demonstrate a setting in which the memory of allograft tolerance dominates over the memory of transplant rejection.

No MeSH data available.


Related in: MedlinePlus

Animals experiencing a return of transplantation tolerance can successfully develop protective immunity to a lethal challenge of Lm.Tolerant (Tol) mice received a primary lethal (L) challenge of Lm (1.2 × 107 CFU; 1° L-Lm, n=10) or a sublethal Lm infection on day 0 (D0) followed by graft rejection and subsequent re-infection with a secondary lethal Lm challenge (2° L-Lm) on D14 or D56 after the first infection (n=7–9 per group). Data are pooled from two independent experiments. (a) Experimental design. (b) Data are presented as percent animal survival after lethal Lm challenge (P<0.001 for 2° L-Lm on D14 or D56 compared with 1° L-Lm by log-rank test).
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f5: Animals experiencing a return of transplantation tolerance can successfully develop protective immunity to a lethal challenge of Lm.Tolerant (Tol) mice received a primary lethal (L) challenge of Lm (1.2 × 107 CFU; 1° L-Lm, n=10) or a sublethal Lm infection on day 0 (D0) followed by graft rejection and subsequent re-infection with a secondary lethal Lm challenge (2° L-Lm) on D14 or D56 after the first infection (n=7–9 per group). Data are pooled from two independent experiments. (a) Experimental design. (b) Data are presented as percent animal survival after lethal Lm challenge (P<0.001 for 2° L-Lm on D14 or D56 compared with 1° L-Lm by log-rank test).

Mentions: The inability of tolerant mice to demonstrate a functional memory of the transplant rejection prompted us to test whether this defect extended to the development of protective immunity to Lm. Lm-infected tolerant animals were challenged with a dose of Lm that was lethal to tolerant recipients that had not been previously infected (Fig. 5a). Memory to Lm developed successfully as the Lm-infected tolerant animals were protected against a lethal challenge of Lm administered either 2 or 8 weeks after the first infection (Fig. 5b). Thus, Lm infection abrogated established transplantation tolerance without inducing a functional allograft-specific memory, whereas anti-Lm memory developed normally.


Spontaneous restoration of transplantation tolerance after acute rejection.

Miller ML, Daniels MD, Wang T, Chen J, Young J, Xu J, Wang Y, Yin D, Vu V, Husain AN, Alegre ML, Chong AS - Nat Commun (2015)

Animals experiencing a return of transplantation tolerance can successfully develop protective immunity to a lethal challenge of Lm.Tolerant (Tol) mice received a primary lethal (L) challenge of Lm (1.2 × 107 CFU; 1° L-Lm, n=10) or a sublethal Lm infection on day 0 (D0) followed by graft rejection and subsequent re-infection with a secondary lethal Lm challenge (2° L-Lm) on D14 or D56 after the first infection (n=7–9 per group). Data are pooled from two independent experiments. (a) Experimental design. (b) Data are presented as percent animal survival after lethal Lm challenge (P<0.001 for 2° L-Lm on D14 or D56 compared with 1° L-Lm by log-rank test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4498267&req=5

f5: Animals experiencing a return of transplantation tolerance can successfully develop protective immunity to a lethal challenge of Lm.Tolerant (Tol) mice received a primary lethal (L) challenge of Lm (1.2 × 107 CFU; 1° L-Lm, n=10) or a sublethal Lm infection on day 0 (D0) followed by graft rejection and subsequent re-infection with a secondary lethal Lm challenge (2° L-Lm) on D14 or D56 after the first infection (n=7–9 per group). Data are pooled from two independent experiments. (a) Experimental design. (b) Data are presented as percent animal survival after lethal Lm challenge (P<0.001 for 2° L-Lm on D14 or D56 compared with 1° L-Lm by log-rank test).
Mentions: The inability of tolerant mice to demonstrate a functional memory of the transplant rejection prompted us to test whether this defect extended to the development of protective immunity to Lm. Lm-infected tolerant animals were challenged with a dose of Lm that was lethal to tolerant recipients that had not been previously infected (Fig. 5a). Memory to Lm developed successfully as the Lm-infected tolerant animals were protected against a lethal challenge of Lm administered either 2 or 8 weeks after the first infection (Fig. 5b). Thus, Lm infection abrogated established transplantation tolerance without inducing a functional allograft-specific memory, whereas anti-Lm memory developed normally.

Bottom Line: Such rejection invariably results in allosensitization and accelerated rejection of secondary donor-matched grafts.When such an allograft is rejected, it has been assumed that the same rules of allosensitization apply as to non-tolerant hosts and that immunological tolerance is permanently lost.Using a mouse model of cardiac transplantation, we show that when Listeria monocytogenes infection precipitates acute rejection, thus abrogating transplantation tolerance, the donor-specific tolerant state re-emerges, allowing spontaneous acceptance of a donor-matched second transplant.

View Article: PubMed Central - PubMed

Affiliation: Section of Rheumatology, Department of Medicine, The University of Chicago, 924 E. 57th Street, JFK-R302, Chicago, Illinois 60637, USA.

ABSTRACT
Transplantation is a cure for end-stage organ failure but, in the absence of pharmacological immunosuppression, allogeneic organs are acutely rejected. Such rejection invariably results in allosensitization and accelerated rejection of secondary donor-matched grafts. Transplantation tolerance can be induced in animals and a subset of humans, and enables long-term acceptance of allografts without maintenance immunosuppression. However, graft rejection can occur long after a state of transplantation tolerance has been acquired. When such an allograft is rejected, it has been assumed that the same rules of allosensitization apply as to non-tolerant hosts and that immunological tolerance is permanently lost. Using a mouse model of cardiac transplantation, we show that when Listeria monocytogenes infection precipitates acute rejection, thus abrogating transplantation tolerance, the donor-specific tolerant state re-emerges, allowing spontaneous acceptance of a donor-matched second transplant. These data demonstrate a setting in which the memory of allograft tolerance dominates over the memory of transplant rejection.

No MeSH data available.


Related in: MedlinePlus