Itacitinib prevents xenogeneic GVHD in humanized mice

Courtois, Justine; Ritacco, Caroline; Dubois, Sophie; Canti, Lorenzo; Vandenhove, Benoît; Seidel, Laurence; Daulne, Coline; Caers, Jo; Servais, Sophie; Béguin, Yves; Ehx, Grégory; Baron, Frédéric

doi:10.1038/s41409-021-01363-1

Cited by 20 publications

(17 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Blockade of JAK1 corresponded to increased human CD4 + and CD8 + T cell engraftment and reduced human Treg engraftment (153). Dual blockade of Aurora Kinase A and JAK2, which are downstream of CD28 and IFN-γ, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor family members, respectively, corresponded to the development of human Th1 and Th17 cells and impairment in human Treg numbers (154).…”

Section: Intracellular Signalling Moleculesmentioning

confidence: 99%

“…Blockade of JAK 1, which is downstream of IL-2, IL-4 and IL-6 receptor family members, demonstrates a role for this kinase in GVHD development. Blockade of JAK 1 corresponded to increased human CD4 + and CD8 + T cell engraftment and reduced human Treg engraftment [ 153 ]. Dual blockade of Aurora Kinase A and JAK 2, which are downstream of CD28 and IFN-γ, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor family members, respectively, impaired the development of human Th1 and Th17 cells and increased human Treg numbers [ 154 ].…”

Section: Cell Signalling Mechanisms In Gvhdmentioning

confidence: 99%

See 1 more Smart Citation

Insights into mechanisms of graft-versus-host disease through humanised mouse models

et al. 2022

View full text Add to dashboard Cite

Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic haematopoietic stem cell transplantation (HSCT) for the treatment of haematological cancers and other blood-related disorders. GVHD is an inflammatory disorder, where the transplanted donor immune cells can mediate an immune response against the recipient and attack host tissues. Despite over 60 years of research, broad-range immune suppression is still used to prevent or treat GVHD, leading to an increased risk of cancer relapse and infection. Therefore, further insights into the disease mechanisms and development of predictive and prognostic biomarkers are key to improving outcomes and reducing GVHD development following allogeneic HSCT. An important preclinical tool to examine the pathophysiology of GVHD, and to understand the key mechanisms that lead to GVHD development, are preclinical humanised mouse models. Such models of GVHD are now well-established and can provide valuable insights into disease development. This review will focus on models where human peripheral blood mononuclear cells are injected into immune-deficient non-obese diabetic (NOD)-scid-interleukin-2(IL-2)Rγ mutant (NOD-scid-IL2Rγnull) mice. Humanised mouse models of GVHD can mimic the clinical setting for GVHD development, with disease progression and tissues impacted like that observed in humans. This review will highlight key findings from preclinical humanised mouse models regarding the role of donor human immune cells, the function of cytokines and cell signalling molecules and their impact on specific target tissues and GVHD development. Further, specific therapeutic strategies tested in these preclinical models reveal key molecular pathways important in reducing the burden of GVHD following allogeneic HSCT.

show abstract

Section: Intracellular Signalling Moleculesmentioning

confidence: 99%

Section: Cell Signalling Mechanisms In Gvhdmentioning

confidence: 99%

Insights into mechanisms of graft-versus-host disease through humanised mouse models

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The JAK3 inhibitor Tofacitinib (CP-690550) was reported to ameliorate GVHD in vivo and in vitro by selectively inhibiting Th1 differentiation but not Th17 polarization or CD4 T cell proliferation (183). Itacitinib (INCB039110), a selective JAK1 inhibitor, disrupts the JAK1/STAT3 signaling pathway and was shown to improve GVHD outcomes and survival in various mouse models, partially by reduction of CD4 and CD8 T cell numbers in the inflamed colon tissue, indicating a loss of Th17 phenotype (178)(179)(180). Itacitinib also showed promising efficiencies in the treatment of steroid-naïve and steroidrefractory GVHD in a first clinical study (201).…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?

Campe

Ullrich

2022

Front. Immunol.

View full text Add to dashboard Cite

Allogenic hematopoietic stem cell transplantation (allo-HSCT) represents a potent and potentially curative treatment for many hematopoietic malignancies and hematologic disorders in adults and children. The donor-derived immunity, elicited by the stem cell transplant, can prevent disease relapse but is also responsible for the induction of graft-versus-host disease (GVHD). The pathophysiology of acute GVHD is not completely understood yet. In general, acute GVHD is driven by the inflammatory and cytotoxic effect of alloreactive donor T cells. Since several experimental approaches indicate that CD4 T cells play an important role in initiation and progression of acute GVHD, the contribution of the different CD4 T helper (Th) cell subtypes in the pathomechanism and regulation of the disease is a central point of current research. Th lineages derive from naïve CD4 T cell progenitors and lineage commitment is initiated by the surrounding cytokine milieu and subsequent changes in the transcription factor (TF) profile. Each T cell subtype has its own effector characteristics, immunologic function, and lineage specific cytokine profile, leading to the association with different immune responses and diseases. Acute GVHD is thought to be mainly driven by the Th1/Th17 axis, whereas Treg cells are attributed to attenuate GVHD effects. As the differentiation of each Th subset highly depends on the specific composition of activating and repressing TFs, these present a potent target to alter the Th cell landscape towards a GVHD-ameliorating direction, e.g. by inhibiting Th1 and Th17 differentiation. The finding, that targeting of Th1 and Th17 differentiation appears more effective for GVHD-prevention than a strategy to inhibit Th1 and Th17 cytokines supports this concept. In this review, we shed light on the current advances of potent TF inhibitors to alter Th cell differentiation and consecutively attenuate GVHD. We will focus especially on preclinical studies and outcomes of TF inhibition in murine GVHD models. Finally, we will point out the possible impact of a Th cell subset-specific immune modulation in context of GVHD.

show abstract

“…Similarly, inhibition of JAK1/JAK3 inhibition also reduced aGVHD and enhanced survival ( 187 ). While significant evidence supports the role of multi-kinase inhibitors that target more than one JAK protein, selective JAK1, JAK2 or JAK3 inhibition is also effective in many GVHD models ( 188 , 193 , 194 ). The impact of JAK inhibitors on GVL activity, however, is variable.…”

Section: Sequential Administration Of Tolerogenic Anti-il-2 and Jak I...mentioning

confidence: 99%

Retention of Donor T Cells in Lymphohematopoietic Tissue and Augmentation of Tissue PD-L1 Protection for Prevention of GVHD While Preserving GVL Activity

et al. 2022

View full text Add to dashboard Cite

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for hematological malignancies (i.e., leukemia and lymphoma) due to the graft-versus-leukemia (GVL) activity mediated by alloreactive T cells that can eliminate residual malignant cells and prevent relapse. However, the same alloreactive T cells can cause a serious side effect, known as graft-versus-host disease (GVHD). GVHD and GVL occur in distinct organ and tissues, with GVHD occurring in target organs (e.g., the gut, liver, lung, skin, etc.) and GVL in lympho-hematopoietic tissues where hematological cancer cells primarily reside. Currently used immunosuppressive drugs for the treatment of GVHD inhibit donor T cell activation and expansion, resulting in a decrease in both GVHD and GVL activity that is associated with cancer relapse. To prevent GVHD, it is important to allow full activation and expansion of alloreactive T cells in the lympho-hematopoietic tissues, as well as prevent donor T cells from migrating into the GVHD target tissues, and tolerize infiltrating T cells via protective mechanisms, such as PD-L1 interacting with PD-1, in the target tissues. In this review, we will summarize major approaches that prevent donor T cell migration into GVHD target tissues and approaches that augment tolerization of the infiltrating T cells in the GVHD target tissues while preserving strong GVL activity in the lympho-hematopoietic tissues.

show abstract

Itacitinib prevents xenogeneic GVHD in humanized mice

Cited by 20 publications

References 36 publications

Insights into mechanisms of graft-versus-host disease through humanised mouse models

Insights into mechanisms of graft-versus-host disease through humanised mouse models

T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?

Retention of Donor T Cells in Lymphohematopoietic Tissue and Augmentation of Tissue PD-L1 Protection for Prevention of GVHD While Preserving GVL Activity

Contact Info

Product

Resources

About