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Extracorporeal Photopheresis: Tolerogenic or Immunogenic Cell Death? Beyond Current Dogma.

Hannani D - Front Immunol (2015)

View Article: PubMed Central - PubMed

Affiliation: PDCline Pharma SAS , Grenoble , France.

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Extracorporeal photopheresis (ECP) is an autologous cell therapy that is widely used for the treatment of T cell-mediated diseases... ECP has been FDA-approved for the treatment of cutaneous T cell lymphoma (CTCL) and has shown potent clinical benefits in various other (non-cancer) T cell-mediated diseases, such as graft versus host disease (GvHD), allograft rejection, as well as in autoimmune disorders, such as rheumatoid arthritis, psoriasis, systemic sclerosis, type 1 diabetes, and Crohn’s disease... This repeated process leads to the improvement in patients’ clinical status, allowing the decrease or the disappearance of tumoral T cells in CTCL, or a decrease or a total disruption of immunosuppressive drugs, thus avoiding steroid-related side effects in GvHD... ECP has also shown benefits in cortico-refractory patients... Indeed, Gatza et al. have described that the injection of ECP-treated splenocytes from mice developing GvHD (i.e., containing allogeneic T cells) triggers IL-10-producing regulatory T cells (Tregs) able to reverse experimental GvHD... However, authors did not assess whether or not ECP-induced Tregs were alloantigen specific (i.e., that ECP does not induces a systemic tolerance in this setting) in order to fully recapitulate the clinical situation observed in humans... Altogether these data indicate that ECP might be able to induce, at least in part, immune tolerance... However, the generation of Tregs as a unique mechanism neither explains how ECP selectively targets pathogenic T cells without inducing a systemic immunosuppression nor how it works in CTCL... Ayyildiz et al. have reported that the serum TNF-α level decrease 1 day after ECP treatment in chronic GvHD... Interestingly, during the first ECP treatments, the serum TNF-α level fluctuates and it is found as high as baseline prior to the second ECP treatment... It is likely that ECP first induces a transient immune tolerance due to the infusion of large quantity of apoptotic cells, as described in other settings... However, following several ECP sessions, the serum TNF-α level tends to stably decrease in responding patients... It is conceivable that ECP-induced transient immune tolerance could be paralleled and/or followed by the generation of anti-clonotypic responses, which would indirectly trigger a steady TNF-α decrease by eliminating pathogenic T cells... Indeed, ECP-induced ICD of pathogenic T cells could reconcile the apparently contradictory MoAs proposed so far (triggering immunity in CTCL and immune tolerance in GvHD).

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Related in: MedlinePlus

ECP-induced anti-clonotypic response in GvHD. (1) (Oligo)clonal activated alloreactive T cells are enriched compared to «normal» resting T cells among treated cells. (2) Cells are re-infused back to the patient. (3) Activated T cells undergo apoptosis faster than resting T cells. (4) Emission of immunogenic signals. (5) During this window of time, dying activated T cells will be preferentially phagocytized by dendritic cells (DCs), representing the main source of antigen. (6) DCs will then process and present alloreactive associated T cells antigens (i.e., TcR-derived peptides), allowing the elicitation of an anti-clonotypic response. (7) Anti-clonotypic T cells will then specifically recognize and eradicate alloreactive T cells. (8) The eradication of alloreactive T cells will lead to the improvement of GvHD without inducing systemic immunosuppression.
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Figure 1: ECP-induced anti-clonotypic response in GvHD. (1) (Oligo)clonal activated alloreactive T cells are enriched compared to «normal» resting T cells among treated cells. (2) Cells are re-infused back to the patient. (3) Activated T cells undergo apoptosis faster than resting T cells. (4) Emission of immunogenic signals. (5) During this window of time, dying activated T cells will be preferentially phagocytized by dendritic cells (DCs), representing the main source of antigen. (6) DCs will then process and present alloreactive associated T cells antigens (i.e., TcR-derived peptides), allowing the elicitation of an anti-clonotypic response. (7) Anti-clonotypic T cells will then specifically recognize and eradicate alloreactive T cells. (8) The eradication of alloreactive T cells will lead to the improvement of GvHD without inducing systemic immunosuppression.

Mentions: Extracorporeal photopheresis-induced ICD would support the anti-clonotypic response hypothesis in CTCL. Indeed, the re-infusion of tumoral T cells undergoing ICD back to the patient would facilitate DC-mediated phagocytosis as well as DC maturation. Of note, Yakut et al. have shown that ECP actually promotes IL-1β production by ECP-treated DCs (31). Since IL-1β is a key cytokine involved in ICD-induced anti-tumor responses (23, 24, 27), IL-1β-producing DCs would be, in turn, able to initiate an anti-tumor immune response directed toward living cancer cells. Importantly, ECP-induced ICD could also support this hypothesis in GvHD (and solid organ transplantation and autoimmunity disorders) as well. Indeed, in these pathologies, oligoclonal pathogenic T cells may represent an important proportion of circulating T cells – therefore, an important proportion among treated cells – and are in an activated state (because of undergoing allo- or auto-immunity). Interestingly, it has been shown that activated T cells die more rapidly than resting T cells following ECP treatment (32). It means that during the first hours following re-infusion of treated cells, only pathogenic T cells undergo (immunogenic?) cell death. In these conditions, they become the unique source of antigens. Thus, this window of time allows the preferential phagocytosis of dying pathogenic T cells by APCs, and subsequent antigen processing and presentation to the immune system. Of note, Johansson and colleagues have shown that in presence of activated, but not resting, apoptotic T cells, autologous DCs acquired a mature phenotype and produce pro-inflammatory cytokines (33). Importantly, DCs exposed to allogeneic, activated apoptotic T cells induce the proliferation and IFNγ production by autologous T cells. In this setting, pathogenic activated T cell TcR-derived peptides could be presented to the immune system, leading to the elicitation of an anti-(oligo)clonotypic immune response, targeting the pathogenic (oligo)clonal T cell population (Figure 1). This scenario would explain why the presence of pathogenic T cells is critical for reaching therapeutic success, as well as, how ECP induces a specific control of alloreactive T cells responsible for GvHD and solid organ rejection, or autoimmune T cells involved in autoimmune disorders, without inducing generalized immunosuppression (i.e., by eradicating specifically the pathogenic T cells). Ayyildiz et al. have reported that the serum TNF-α level decrease 1 day after ECP treatment in chronic GvHD (34). Interestingly, during the first ECP treatments, the serum TNF-α level fluctuates and it is found as high as baseline prior to the second ECP treatment. It is likely that ECP first induces a transient immune tolerance due to the infusion of large quantity of apoptotic cells, as described in other settings (11, 13). However, following several ECP sessions, the serum TNF-α level tends to stably decrease in responding patients (34). It is conceivable that ECP-induced transient immune tolerance could be paralleled and/or followed by the generation of anti-clonotypic responses, which would indirectly trigger a steady TNF-α decrease by eliminating pathogenic T cells. Indeed, ECP-induced ICD of pathogenic T cells could reconcile the apparently contradictory MoAs proposed so far (triggering immunity in CTCL and immune tolerance in GvHD). Understanding ECPs MoA will help considerably in rationalizing treatment schedules and processes as well as its application field. Finally, it is a critical step toward identifying a predictive biomarker of efficacy for improving the patients’ response rates and for proposing synergizing combinatory therapy for rescuing unresponsive patients.


Extracorporeal Photopheresis: Tolerogenic or Immunogenic Cell Death? Beyond Current Dogma.

Hannani D - Front Immunol (2015)

ECP-induced anti-clonotypic response in GvHD. (1) (Oligo)clonal activated alloreactive T cells are enriched compared to «normal» resting T cells among treated cells. (2) Cells are re-infused back to the patient. (3) Activated T cells undergo apoptosis faster than resting T cells. (4) Emission of immunogenic signals. (5) During this window of time, dying activated T cells will be preferentially phagocytized by dendritic cells (DCs), representing the main source of antigen. (6) DCs will then process and present alloreactive associated T cells antigens (i.e., TcR-derived peptides), allowing the elicitation of an anti-clonotypic response. (7) Anti-clonotypic T cells will then specifically recognize and eradicate alloreactive T cells. (8) The eradication of alloreactive T cells will lead to the improvement of GvHD without inducing systemic immunosuppression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493405&req=5

Figure 1: ECP-induced anti-clonotypic response in GvHD. (1) (Oligo)clonal activated alloreactive T cells are enriched compared to «normal» resting T cells among treated cells. (2) Cells are re-infused back to the patient. (3) Activated T cells undergo apoptosis faster than resting T cells. (4) Emission of immunogenic signals. (5) During this window of time, dying activated T cells will be preferentially phagocytized by dendritic cells (DCs), representing the main source of antigen. (6) DCs will then process and present alloreactive associated T cells antigens (i.e., TcR-derived peptides), allowing the elicitation of an anti-clonotypic response. (7) Anti-clonotypic T cells will then specifically recognize and eradicate alloreactive T cells. (8) The eradication of alloreactive T cells will lead to the improvement of GvHD without inducing systemic immunosuppression.
Mentions: Extracorporeal photopheresis-induced ICD would support the anti-clonotypic response hypothesis in CTCL. Indeed, the re-infusion of tumoral T cells undergoing ICD back to the patient would facilitate DC-mediated phagocytosis as well as DC maturation. Of note, Yakut et al. have shown that ECP actually promotes IL-1β production by ECP-treated DCs (31). Since IL-1β is a key cytokine involved in ICD-induced anti-tumor responses (23, 24, 27), IL-1β-producing DCs would be, in turn, able to initiate an anti-tumor immune response directed toward living cancer cells. Importantly, ECP-induced ICD could also support this hypothesis in GvHD (and solid organ transplantation and autoimmunity disorders) as well. Indeed, in these pathologies, oligoclonal pathogenic T cells may represent an important proportion of circulating T cells – therefore, an important proportion among treated cells – and are in an activated state (because of undergoing allo- or auto-immunity). Interestingly, it has been shown that activated T cells die more rapidly than resting T cells following ECP treatment (32). It means that during the first hours following re-infusion of treated cells, only pathogenic T cells undergo (immunogenic?) cell death. In these conditions, they become the unique source of antigens. Thus, this window of time allows the preferential phagocytosis of dying pathogenic T cells by APCs, and subsequent antigen processing and presentation to the immune system. Of note, Johansson and colleagues have shown that in presence of activated, but not resting, apoptotic T cells, autologous DCs acquired a mature phenotype and produce pro-inflammatory cytokines (33). Importantly, DCs exposed to allogeneic, activated apoptotic T cells induce the proliferation and IFNγ production by autologous T cells. In this setting, pathogenic activated T cell TcR-derived peptides could be presented to the immune system, leading to the elicitation of an anti-(oligo)clonotypic immune response, targeting the pathogenic (oligo)clonal T cell population (Figure 1). This scenario would explain why the presence of pathogenic T cells is critical for reaching therapeutic success, as well as, how ECP induces a specific control of alloreactive T cells responsible for GvHD and solid organ rejection, or autoimmune T cells involved in autoimmune disorders, without inducing generalized immunosuppression (i.e., by eradicating specifically the pathogenic T cells). Ayyildiz et al. have reported that the serum TNF-α level decrease 1 day after ECP treatment in chronic GvHD (34). Interestingly, during the first ECP treatments, the serum TNF-α level fluctuates and it is found as high as baseline prior to the second ECP treatment. It is likely that ECP first induces a transient immune tolerance due to the infusion of large quantity of apoptotic cells, as described in other settings (11, 13). However, following several ECP sessions, the serum TNF-α level tends to stably decrease in responding patients (34). It is conceivable that ECP-induced transient immune tolerance could be paralleled and/or followed by the generation of anti-clonotypic responses, which would indirectly trigger a steady TNF-α decrease by eliminating pathogenic T cells. Indeed, ECP-induced ICD of pathogenic T cells could reconcile the apparently contradictory MoAs proposed so far (triggering immunity in CTCL and immune tolerance in GvHD). Understanding ECPs MoA will help considerably in rationalizing treatment schedules and processes as well as its application field. Finally, it is a critical step toward identifying a predictive biomarker of efficacy for improving the patients’ response rates and for proposing synergizing combinatory therapy for rescuing unresponsive patients.

View Article: PubMed Central - PubMed

Affiliation: PDCline Pharma SAS , Grenoble , France.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Extracorporeal photopheresis (ECP) is an autologous cell therapy that is widely used for the treatment of T cell-mediated diseases... ECP has been FDA-approved for the treatment of cutaneous T cell lymphoma (CTCL) and has shown potent clinical benefits in various other (non-cancer) T cell-mediated diseases, such as graft versus host disease (GvHD), allograft rejection, as well as in autoimmune disorders, such as rheumatoid arthritis, psoriasis, systemic sclerosis, type 1 diabetes, and Crohn’s disease... This repeated process leads to the improvement in patients’ clinical status, allowing the decrease or the disappearance of tumoral T cells in CTCL, or a decrease or a total disruption of immunosuppressive drugs, thus avoiding steroid-related side effects in GvHD... ECP has also shown benefits in cortico-refractory patients... Indeed, Gatza et al. have described that the injection of ECP-treated splenocytes from mice developing GvHD (i.e., containing allogeneic T cells) triggers IL-10-producing regulatory T cells (Tregs) able to reverse experimental GvHD... However, authors did not assess whether or not ECP-induced Tregs were alloantigen specific (i.e., that ECP does not induces a systemic tolerance in this setting) in order to fully recapitulate the clinical situation observed in humans... Altogether these data indicate that ECP might be able to induce, at least in part, immune tolerance... However, the generation of Tregs as a unique mechanism neither explains how ECP selectively targets pathogenic T cells without inducing a systemic immunosuppression nor how it works in CTCL... Ayyildiz et al. have reported that the serum TNF-α level decrease 1 day after ECP treatment in chronic GvHD... Interestingly, during the first ECP treatments, the serum TNF-α level fluctuates and it is found as high as baseline prior to the second ECP treatment... It is likely that ECP first induces a transient immune tolerance due to the infusion of large quantity of apoptotic cells, as described in other settings... However, following several ECP sessions, the serum TNF-α level tends to stably decrease in responding patients... It is conceivable that ECP-induced transient immune tolerance could be paralleled and/or followed by the generation of anti-clonotypic responses, which would indirectly trigger a steady TNF-α decrease by eliminating pathogenic T cells... Indeed, ECP-induced ICD of pathogenic T cells could reconcile the apparently contradictory MoAs proposed so far (triggering immunity in CTCL and immune tolerance in GvHD).

No MeSH data available.


Related in: MedlinePlus