Heterologous immunity provides a potent barrier to transplantation tolerance

Adams, Andrew; Williams, Matthew A.; Jones, Thomas R.; Shirasugi, Nozomu; Durham, Megan M.; Kaech, Susan M.; Wherry, E. John; Onami, Thandi M.; Lanier, J. Gibson; Kokko, Kenneth E.; Pearson, Thomas C.; Ahmed, Rafi; Larsen, Christian

doi:10.1172/jci17477

Cited by 295 publications

(356 citation statements)

References 48 publications

Supporting

Mentioning

345

Contrasting

Unclassified

Order By: Relevance

“…In the 1990s, Akbar and coworkers described host memory T cells displaying reactivity against donor kidney alloantigens in patients with acute rejection (Akbar et al 1990). This was supposed to result from degeneracy of the memory T-cell repertoire (TCR), resulting in heterologous immunity (alloreactivity of the TCR to unrelated antigens as a result of previous immunological exposure) (reviewed in Adams et al 2003a;Adams et al 2003b). Moreover, current "induction" drugs, which are responsible for a drastic lymphopenia in graft recipients, may induce a wave of memory-like cells (homeostatic proliferation) with exacerbated functions against donor alloantigens (Moxham et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Interleukin 7 receptor α as a potential therapeutic target in transplantation

Racapé

Vanhove

Soulillou

et al. 2009

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

Drugs targeting memory lymphocytes may allow for a better control of rejection in transplantation, particularly in immunized patients. In this article the rationale of targeting interleukin 7 receptor alpha (IL-7Ralpha), a molecule expressed by both memory and naive T cells, is reviewed in the context of transplantation. Whereas naive T cells are partly responsible for acute rejection and are targeted by current immunosuppressive drugs that block costimulatory signals (cyclosporine A, anti-CD3 antibody, anti-CD52 antibody, anti-thymocyte globulin, etc.), memory T cells are resistant to costimulation blockade. As such, memory cells are an obstacle to experimental tolerance induction and may be involved in chronic rejection. There is thus much scientific interest in developing molecules able to target these cells. The role of the IL-7/IL-7Ralpha pathway in transplantation rejection has been suggested by the effect of an anti-IL-7 monoclonal antibody which, when associated with costimulation blockade, prolonged heart allograft survival in mice. Here the hypothesis that targeting IL-7Ralpha would preserve effector T cells that are less dependent on IL-7 for survival while sparing regulatory CD4+ CD25high IL-7Ralpha(low) T cells is discussed. An anti-IL-7Ralpha antibody could also help achieve allograft tolerance by reducing alloreactive cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Interleukin 7 receptor α as a potential therapeutic target in transplantation

Racapé

Vanhove

Soulillou

et al. 2009

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

show abstract

“…It has been recognized recently that memory T cells developed in response to immunization with one particular antigen can respond to other unrelated antigens, thereby affecting the subsequent memory responses to a wide range of different antigens, and this phenomenon is called heterologous immunity [30]. In transplant settings, there is solid evidence demonstrating that memory T cells that are specific to pathogens such as Leishmania major or lymphocytic choriomeningitis virus can respond to a defined set of transplant antigens [1,23]. A major implication of heterologous immunity is that in humans with a normal history of vaccinations and infections, memory T cells that are potentially reactive to transplant antigens may be numerous.…”

Section: Unique Features Of Memory T Cellsmentioning

confidence: 99%

“…Similarly, adoptive transfer of primed donor-specific T cells into recipient mice prevents the induction of cardiac allograft tolerance in naïve mice by the DST and MR1 protocol [37]. Other costimulation blockade-based tolerizing protocols also fail to induce tolerance in mice harboring memory T cells specific for pathogens [1,23]. The role of pathogen-specific memory T cells that are cross-reactive with alloantigens in resistance to tolerance induction is elegantly demonstrated in a recent report showing that virally induced memory T cells can interfere with the most robust form of transplant tolerance [1].…”

Section: Clearly Memory T Cells Are Potent Effector Cells In Transplmentioning

confidence: 99%

“…Other costimulation blockade-based tolerizing protocols also fail to induce tolerance in mice harboring memory T cells specific for pathogens [1,23]. The role of pathogen-specific memory T cells that are cross-reactive with alloantigens in resistance to tolerance induction is elegantly demonstrated in a recent report showing that virally induced memory T cells can interfere with the most robust form of transplant tolerance [1]. Hence, memory T cells generated either by prior exposure to alloantigens or by pathogen infections are potent barriers to tolerance induction in transplant models.…”

Section: Clearly Memory T Cells Are Potent Effector Cells In Transplmentioning

confidence: 99%

“…For example, the NF-κB nuclear translocation blocker 15-deoxyspergualin prevented activation of donor antigen-specific memory CD8 T cells and synergized with costimulatory blockade to induce long-term skin allograft survival in a mouse model [1]. Administration of the sphingosine-1 phosphate receptor agonist FTY720 resulted in lymphoid sequestration of donor-specific memory CD4 T cells in the peripheral lymph nodes, thus delaying the heart allograft rejection in mice [42].…”

Section: New Approaches To Targeting Alloreactive Memory T Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Approaches and challenges in targeting memory T cells in transplant tolerance

Chen

2007

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

Memory T cells are an important cell type in the immune system and are vital to protective immunity against invading pathogens. However, a significant fraction of memory T cells is found to be alloreactive in transplant models, i.e. they can readily attack and dismantle allografts in transplant models. As memory T cells are not as easily amenable as naive T cells, memory T cells constitute a potent barrier to the induction of transplant tolerance. The key issues concerning memory T cells in transplantation are related to the tolerability of alloreactive memory T cells and the effects of commonly used immunosuppressive drugs on the memory response in transplant recipients. The real challenge in the future is to selectively tolerize alloreactive memory T cells but spare those involved in protective immunity following organ transplantation. This review will discuss recent advances in our understating of memory T cells in transplant models, with specific emphasis on the problems and challenges in targeting memory T cells in the induction of transplant tolerance.

show abstract

Regulatory T cells can prevent memory CD8⁺ T‐cell‐mediated rejection following polymorphonuclear cell depletion

et al. 2010

View full text Add to dashboard Cite

Accumulating evidence suggests that alloreactive memory T cells (Tm) may form a barrier to tolerance induction in large animals and humans due in part to a resistance to suppression by Treg. However, why Tm are resistant to regulation and how the Tm response to an allograft differs from that of naïve T cells, which are amenable to suppression by Treg, remains unknown. Here, we show that accelerated graft rejection mediated by CD8+ Tm was due to the enhanced recruitment of PMN to allografts in a mouse skin allograft model. Importantly, depletion of PMN slowed the kinetics of (but did not prevent) rejection mediated by Tm and created a window of opportunity that allowed subsequent suppression of rejection by Treg. Taken together, we conclude that CD8+ Tm are not intrinsically resistant to suppression by Treg but may rapidly inflict substantial graft damage before the establishment of regulatory mechanisms. These data suggest that if Tm responses can be attenuated transiently following transplantation, Treg may be able to maintain tolerance through the suppression of both memory and naïve alloreactive T-cell responses in the long term.

show abstract

Heterologous immunity provides a potent barrier to transplantation tolerance

Cited by 295 publications

References 48 publications

Interleukin 7 receptor α as a potential therapeutic target in transplantation

Interleukin 7 receptor α as a potential therapeutic target in transplantation

Approaches and challenges in targeting memory T cells in transplant tolerance

Regulatory T cells can prevent memory CD8⁺ T‐cell‐mediated rejection following polymorphonuclear cell depletion

Contact Info

Product

Resources

About

Heterologous immunity provides a potent barrier to transplantation tolerance

Cited by 295 publications

References 48 publications

Interleukin 7 receptor α as a potential therapeutic target in transplantation

Interleukin 7 receptor α as a potential therapeutic target in transplantation

Approaches and challenges in targeting memory T cells in transplant tolerance

Regulatory T cells can prevent memory CD8+ T‐cell‐mediated rejection following polymorphonuclear cell depletion

Contact Info

Product

Resources

About

Regulatory T cells can prevent memory CD8⁺ T‐cell‐mediated rejection following polymorphonuclear cell depletion