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Dendritic cell-based approaches for therapeutic immune regulation in solid-organ transplantation.

Vassalli G - J Transplant (2013)

Bottom Line: While mature dendritic cells (DCs) present donor antigen to the immune system, triggering rejection, regulatory DCs interact with regulatory T cells to promote immune tolerance.DCs can be treated with pharmacological agents before injection, which may attenuate their maturation in vivo.Genetically engineered DCs have also been tested.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland ; Molecular Cardiology Laboratory, Fondazione Cardiocentro Ticino, 6900 Lugano, Switzerland.

ABSTRACT
To avoid immune rejection, allograft recipients require drug-based immunosuppression, which has significant toxicity. An emerging approach is adoptive transfer of immunoregulatory cells. While mature dendritic cells (DCs) present donor antigen to the immune system, triggering rejection, regulatory DCs interact with regulatory T cells to promote immune tolerance. Intravenous injection of immature DCs of either donor or host origin at the time of transplantation have prolonged allograft survival in solid-organ transplant models. DCs can be treated with pharmacological agents before injection, which may attenuate their maturation in vivo. Recent data suggest that injected immunosuppressive DCs may inhibit allograft rejection, not by themselves, but through conventional DCs of the host. Genetically engineered DCs have also been tested. Two clinical trials in type-1 diabetes and rheumatoid arthritis have been carried out, and other trials, including one trial in kidney transplantation, are in progress or are imminent.

No MeSH data available.


Related in: MedlinePlus

Regulatory T cells (Tregs) are present in the host at the time of transplantation and are recruited to the allograft. They respond to donor alloantigen through cross-reactivity and inhibit T-cell proliferation in draining lymphoid tissue. Tolerogenic DCs favor the generation of Tregs from naive T cells, which then block effector T-cell proliferation while also triggering apoptosis of these cells. They inhibit TH1 cells. These processes facilitate allograft acceptance through several mechanisms including the production and release of immunosuppressive cytokines, such as IL-10 and TGFβ (modified from Wood et al. [2]).
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fig1: Regulatory T cells (Tregs) are present in the host at the time of transplantation and are recruited to the allograft. They respond to donor alloantigen through cross-reactivity and inhibit T-cell proliferation in draining lymphoid tissue. Tolerogenic DCs favor the generation of Tregs from naive T cells, which then block effector T-cell proliferation while also triggering apoptosis of these cells. They inhibit TH1 cells. These processes facilitate allograft acceptance through several mechanisms including the production and release of immunosuppressive cytokines, such as IL-10 and TGFβ (modified from Wood et al. [2]).

Mentions: DC and monocyte lineages originate from a common monocyte and DC progenitor (MDP) that gives rise to monocytes and committed DC progenitors (CDPs) in the bone marrow. CDPs then give rise to pre-DCs that migrate to lymphoid and nonlymphoid tissue and differentiate into the two major populations of lymphoid tissue DCs and nonlymphoid tissue CD103+ DCs [22, 23, 40]. Acting as antigen-presenting cells, DCs trigger innate and adaptive immune responses to microbial antigens and alloantigens, as well as to self-antigens in autoimmune diseases. DCs initiate the innate immune response through activation of NK cells. They also set off the adaptive immune response through activation of naive B and T lymphocytes. Besides their traditional role as immunogenic cells, DCs regulate the immune reaction and mediate peripheral T-cell unresponsiveness under homeostatic conditions in vivo [41]. The regulatory activity of DCs can be accounted for by multiple mechanisms including the production and release of anti-inflammatory cytokines [32], Fas/Fas-ligand-induced apoptosis of effector immune cells [42], deletion, and induction of Tregs [39, 43–46] (Figure 1). Tolerogenic DCs comprise a majority of immature DCs and subpopulations of DCs with various maturation stages, including plasmacytoid DCs [43]. However, a major drawback in vivo is the potential of tolerogenic DCs to mature during infections or inflammation, which would convert them into immunogenic cells [47].


Dendritic cell-based approaches for therapeutic immune regulation in solid-organ transplantation.

Vassalli G - J Transplant (2013)

Regulatory T cells (Tregs) are present in the host at the time of transplantation and are recruited to the allograft. They respond to donor alloantigen through cross-reactivity and inhibit T-cell proliferation in draining lymphoid tissue. Tolerogenic DCs favor the generation of Tregs from naive T cells, which then block effector T-cell proliferation while also triggering apoptosis of these cells. They inhibit TH1 cells. These processes facilitate allograft acceptance through several mechanisms including the production and release of immunosuppressive cytokines, such as IL-10 and TGFβ (modified from Wood et al. [2]).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824554&req=5

fig1: Regulatory T cells (Tregs) are present in the host at the time of transplantation and are recruited to the allograft. They respond to donor alloantigen through cross-reactivity and inhibit T-cell proliferation in draining lymphoid tissue. Tolerogenic DCs favor the generation of Tregs from naive T cells, which then block effector T-cell proliferation while also triggering apoptosis of these cells. They inhibit TH1 cells. These processes facilitate allograft acceptance through several mechanisms including the production and release of immunosuppressive cytokines, such as IL-10 and TGFβ (modified from Wood et al. [2]).
Mentions: DC and monocyte lineages originate from a common monocyte and DC progenitor (MDP) that gives rise to monocytes and committed DC progenitors (CDPs) in the bone marrow. CDPs then give rise to pre-DCs that migrate to lymphoid and nonlymphoid tissue and differentiate into the two major populations of lymphoid tissue DCs and nonlymphoid tissue CD103+ DCs [22, 23, 40]. Acting as antigen-presenting cells, DCs trigger innate and adaptive immune responses to microbial antigens and alloantigens, as well as to self-antigens in autoimmune diseases. DCs initiate the innate immune response through activation of NK cells. They also set off the adaptive immune response through activation of naive B and T lymphocytes. Besides their traditional role as immunogenic cells, DCs regulate the immune reaction and mediate peripheral T-cell unresponsiveness under homeostatic conditions in vivo [41]. The regulatory activity of DCs can be accounted for by multiple mechanisms including the production and release of anti-inflammatory cytokines [32], Fas/Fas-ligand-induced apoptosis of effector immune cells [42], deletion, and induction of Tregs [39, 43–46] (Figure 1). Tolerogenic DCs comprise a majority of immature DCs and subpopulations of DCs with various maturation stages, including plasmacytoid DCs [43]. However, a major drawback in vivo is the potential of tolerogenic DCs to mature during infections or inflammation, which would convert them into immunogenic cells [47].

Bottom Line: While mature dendritic cells (DCs) present donor antigen to the immune system, triggering rejection, regulatory DCs interact with regulatory T cells to promote immune tolerance.DCs can be treated with pharmacological agents before injection, which may attenuate their maturation in vivo.Genetically engineered DCs have also been tested.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland ; Molecular Cardiology Laboratory, Fondazione Cardiocentro Ticino, 6900 Lugano, Switzerland.

ABSTRACT
To avoid immune rejection, allograft recipients require drug-based immunosuppression, which has significant toxicity. An emerging approach is adoptive transfer of immunoregulatory cells. While mature dendritic cells (DCs) present donor antigen to the immune system, triggering rejection, regulatory DCs interact with regulatory T cells to promote immune tolerance. Intravenous injection of immature DCs of either donor or host origin at the time of transplantation have prolonged allograft survival in solid-organ transplant models. DCs can be treated with pharmacological agents before injection, which may attenuate their maturation in vivo. Recent data suggest that injected immunosuppressive DCs may inhibit allograft rejection, not by themselves, but through conventional DCs of the host. Genetically engineered DCs have also been tested. Two clinical trials in type-1 diabetes and rheumatoid arthritis have been carried out, and other trials, including one trial in kidney transplantation, are in progress or are imminent.

No MeSH data available.


Related in: MedlinePlus