Flt3-Ligand Treatment Prevents Diabetes in NOD Mice

Chilton, Paula M.; Rezzoug, Francine; Fugier-Vivier, Isabelle; Weeter, Leslie A.; Xu, Hong; Huang, Yiming; Ray, Mukunda B.; Ildstad, Suzanne T.

doi:10.2337/diabetes.53.8.1995

Cited by 43 publications

(36 citation statements)

References 20 publications

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“…Previous reports suggested the risk that systemically administered FLT3L could induce immunotolerance in vivo by increasing immature DCs (17)(18)(19)(20)(21), although others reported contrary findings (4,15). These conflicting data suggest that FLT3L may give rise to immunotolerance if administered systemically, and the enhancement of tumor immunity mainly depends on the circumstances where local immune response is evoked.…”

Section: Discussionmentioning

confidence: 45%

“…FLT3L is known to cause proliferation of hematopoietic stem cells in vitro (12,13) and as a result, systemic administration of soluble FLT3L, which increases circulating numbers of dendritic cells (DCs) and natural killer (NK) cells, enhances anti-tumoral and viral immunity in vivo (3,(14)(15)(16). However, systemic FLT3L administration may also cause tolerance because of the increased number of immature DCs (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

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Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: Utilization for ovarian cancer treatment

Matsumura

Mandai²,

Hamanishi³

et al. 2008

Oncol Rep

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Abstract. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L) has been considered to be a major route of delivery for tumor immunotherapy because expression of its receptor, FLT3, was detected predominantly in hematopoetic progenitor cells. However, several studies indicate that FLT3L locally overexpressed in tumor or dendritic cells (DCs) also shows an anti-tumor effect. In the current study, we found that FLT3 expression is not present in monocytes but is instead induced in DCs through the differentiation process resulting from stimulation by GM-CSF and IL-4. Addition of FLT3L further augmented FLT3 induction and also increased CD40 expression in DCs, leading to enhanced induction of lymphoblastoid cell line-targeted cytotoxic Tlymphocyte response and CD107a mobilization in CD8 + T cells. Furthermore, FLT3L also induced FLT3 expression in peripheral blood NK cells that showed an enhanced response detected by CD107a mobilization. In a murine ovarian cancer model, locally expressed FLT3L showed anti-tumor effects. Collectively, the current study indicates that FLT3L has an immunostimulatory effect on peripheral blood cells and FLT3L targeted to mature peripheral blood cells may serve as a useful tool for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: Utilization for ovarian cancer treatment

Matsumura

Mandai²,

Hamanishi³

et al. 2008

Oncol Rep

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“…Furthermore, in the latter scenario an antigen targeted to any CD8 Ϫ DC subset might not be cross-presented at all. Because different DC types may play distinct roles in induction of immunity and tolerance (6,(20)(21)(22)(23)) the outcome of the vaccination strategy in each scenario might vary (17).In this study we show that, of the three splenic DC subsets, CD8 ϩ DC are the most efficient at cross-presentation of cellular, soluble, or latex bead-associated antigens. This ability does not appear to be dictated solely by their capacity to capture the antigen, because all three subsets efficiently presented all these forms of antigen by the MHC class II pathway.…”

mentioning

confidence: 74%

mentioning

confidence: 99%

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

Schnorrer¹,

Behrens²,

Wilson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

354

347

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Mouse spleens contain three populations of conventional (CD11c high ) dendritic cells (DCs) that play distinct functions. The CD8 ؉ DC are unique in that they can present exogenous antigens on their MHC class I molecules, a process known as cross-presentation. It is unclear whether this special ability is because only the CD8 ؉ DC can capture the antigens used in cross-presentation assays, or because this is the only DC population that possesses specialized machinery for cross-presentation. To solve this important question we examined the splenic DC subsets for their ability to both present via MHC class II molecules and cross-present via MHC class I using four different forms of the model antigen ovalbumin (OVA). These forms include a cell-associated form, a soluble form, OVA expressed in bacteria, or OVA bound to latex beads. With the exception of bacterial antigen, which was poorly cross-presented by all DC, all antigenic forms were cross-presented much more efficiently by the CD8 ؉ DC. This pattern could not be attributed simply to a difference in antigen capture because all DC subsets presented the antigen via MHC class II. Indeed, direct assessments of endocytosis showed that CD8 ؉ and CD8 ؊ DC captured comparable amounts of soluble and bead-associated antigen, yet only the CD8 ؉ DC cross-presented these antigenic forms. Our results indicate that cross-presentation requires specialized machinery that is expressed by CD8 ؉ DC but largely absent from CD8 ؊ DC. This conclusion has important implications for the design of vaccination strategies based on antigen targeting to DC.antigen presentation ͉ mice ͉ endocytosis ͉ ovalbumin ͉ vaccines D endritic cells (DC) possess several mechanisms that make them highly efficient antigen-presenting cells. DC can endocytose a large variety of exogenous antigens for presentation via MHC class II molecules and for cross-presentation via MHC class I (1). The cross-presenting capacity of DC is unusual, because most other cell types are only able to present endogenous antigens (i.e., antigens synthesized by the antigenpresenting cells themselves) on their MHC class I molecules. Thus, DC possess specialized machinery, as yet not fully defined, that allows delivery of exogenous antigens into the MHC class I presentation pathway for cross-presentation (2, 3).On the other hand, several populations of DC have been described (4, 5), and it is unclear whether all these DC types can cross-present (6). Mouse spleens contain three ''conventional'' (CD11c high ) DC subsets: CD8 ϩ DC, CD4 ϩ DC, and CD4 Ϫ CD8 Ϫ [double negative (DN)] DC. Previous studies have shown that cell-associated antigen was cross-presented by CD8 ϩ but not CD8 Ϫ DC (7-10). The unique capacity of the CD8 ϩ DC at cross-presenting this form of antigen was attributed to their ability to capture dead cells (7-9, 11, 12) because antigens in soluble or immunocomplexed form, or associated to bacteria, were reportedly cross-presented by both CD8 ϩ and CD8 Ϫ DC (8, 9, 13). These findings led to the hypothesis that all DC can...

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“…A number of autoimmune diseases have been successfully treated via bone marrow transplantation (BMT) in rodents and humans. [1][2][3] Both full 2,4 and mixed 5 allogeneic chimerism interrupts disease progression and reverses the autoimmune pathogenesis. 2,4 Theoretically, BMT can be applied to treat type 1 diabetes via 2 mechanisms: (1) through reversal of the autoimmune processes that lead to islet cell destruction; and (2) through the induction of donorspecific tolerance to islet cell transplants.…”

Section: Introductionmentioning

confidence: 99%

Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of αβ-TCR+ and CD4+ cells negates the effect

Ildstad

Chilton

et al. 2005

Blood

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Bone marrow transplantation blocks diabetes pathogenesis and reverses autoimmunity in nonobese diabetic (NOD) mice. However, there is a greater barrier to engraftment in the context of autoimmunity. In the present study, we characterized which recipient cells influence engraftment in prediabetic NOD mice, with the goal to replace myelotoxic conditioning with antigen-specific deletion of reactive host cells. Preconditioning of NOD mice with anti-CD8 and anti-CD154 monoclonal antibodies (mAbs) synergistically enhanced engraftment and significantly reduced the minimum total body irradiation (TBI) dose for engraftment. Strikingly, preconditioning with anti-CD4 mAb significantly impaired engraftment, negating the beneficial effect of anti-CD8, and resulted in a requirement for more TBIbased conditioning compared with controls conditioned with TBI alone. Similarly, more TBI was required when anti-Tcell receptor ␤ (TCR␤) mAb was administered as preconditioning. The addition of anti-CD152 to CD154 preconditioning abrogated the engraftmentenhancing effect of anti-CD154. Taken together, these data indicate a role for CD4 ؉ regulatory T cells in vivo which require signaling via CD152 in the induction of chimerism and tolerance in NOD recipients. Notably, disease prevention and reversal of autoimmunity was absolutely correlated with the establishment of chimerism. These studies have important implications for the design of novel clinical approaches to treat type 1 diabetes. IntroductionType 1 diabetes is an immune-mediated disorder associated with defects in the hematopoietic stem cell (HSC) and/or its progeny. A number of autoimmune diseases have been successfully treated via bone marrow transplantation (BMT) in rodents and humans. [1][2][3] Both full 2,4 and mixed 5 allogeneic chimerism interrupts disease progression and reverses the autoimmune pathogenesis. 2,4 Theoretically, BMT can be applied to treat type 1 diabetes via 2 mechanisms: (1) through reversal of the autoimmune processes that lead to islet cell destruction; and (2) through the induction of donorspecific tolerance to islet cell transplants. The morbidity and mortality associated with current conditioning methods has precluded the widespread use of BMT clinically. 6 Conditioning for BMT has historically been believed to require cytoreduction to prepare vacant niches and immunosuppression to suppress host-versus-graft alloreactivity. Current cytoreductive approaches use agents with broad and nonspecific myelotoxicity. The relative contribution of myelotoxic agents to preparing vacant niches versus controlling the host-versus-graft response is currently controversial. Recent data from nonmyeloablative conditioning models in nonautoimmune recipients suggest that the main role of myelotoxic agents is to control host-versus-graft alloreactivity rather than prepare vacant niches, 7,8 leading to the possibility of developing more benign antigen-driven conditioning strategies. For example, when total body irradiation (TBI) is used as the sole conditioning agent for ...

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Flt3-Ligand Treatment Prevents Diabetes in NOD Mice

Cited by 43 publications

References 20 publications

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: Utilization for ovarian cancer treatment

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: Utilization for ovarian cancer treatment

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of αβ-TCR+ and CD4+ cells negates the effect

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Flt3-Ligand Treatment Prevents Diabetes in NOD Mice

Cited by 43 publications

References 20 publications

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: Utilization for ovarian cancer treatment

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: Utilization for ovarian cancer treatment

The dominant role of CD8+dendritic cells in cross-presentation is not dictated by antigen capture

Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of αβ-TCR+ and CD4+ cells negates the effect

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The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture