Thymic stromal lymphopoietin is not necessary or sufficient to mediate the thymopoietic effects of keratinocyte growth factor

Guimond, Martin; Spolski, Rosanne; Rossi, Simona W.; Veenstra, Rachelle G.; Holländer, Georg A.; Mackall, Crystal L.; Blazar, Bruce R.

doi:10.1182/blood-2007-09-113316

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…Bone marrow transplant (BMT) is a life-saving modality used to treat malignant and nonmalignant disorders. Chemoradiotherapy conditioning, that precedes donor graft infusion, damages thymic and LN stroma, severely delaying peripheral CD4 + and CD8 + T cell reconstitution [ 1 – 3 ]. The endogenous T cell response is defective for 6–24 months post-transplant [ 2 , 4 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

A novel approach to improve immune effector responses post transplant by restoration of CCL21 expression

et al. 2018

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Chemotherapy or chemoradiotherapy conditioning regimens required for bone marrow transplantation (BMT) cause significant morbidity and mortality as a result of insufficient immune surveillance mechanisms leading to increased risks of infection and tumor recurrence. Such conditioning causes host stromal cell injury, impairing restoration of the central (thymus) and peripheral (spleen and lymph node) T cell compartments and slow immune reconstitution. The chemokine, CCL21, produced by host stromal cells, recruits T- and B-cells that provide lymphotoxin mediated instructive signals to stromal cells for lymphoid organogenesis. Moreover, T- and B-cell recruitment into these sites is required for optimal adaptive immune responses to pathogens and tumor antigens. Previously, we reported that CCL21 was markedly reduced in secondary lymphoid organs of transplanted animals. Here, we utilized adenoviral CCL21 gene transduced dendritic cells (DC/CCL21) given by footpad injections as a novel approach to restore CCL21 expression in secondary lymphoid organs post-transplant. CCL21 expression in secondary lymphoid organs reached levels of naïve controls and resulted in increased T cell trafficking to draining lymph nodes (LNs). An increase in both lymphoid tissue inducer cells and the B cell chemokine CXCL13 known to be important in LN formation was observed. Strikingly, only mice vaccinated with DC/CCL21 loaded with bacterial, viral or tumor antigens and not recipients of DC/control adenovirus loaded cells or no DCs had a marked increase in the systemic clearance of pathogens (bacteria; virus) and leukemia cells. Because DC/CCL21 vaccines have been tested in clinical trials for patients with lung cancer and melanoma, our studies provide the foundation for future trials of DC/CCL21 vaccination in patients receiving pre-transplant conditioning regimens.

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Section: Introductionmentioning

confidence: 99%

A novel approach to improve immune effector responses post transplant by restoration of CCL21 expression

et al. 2018

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“…IL-7 promotes the production of T cells and their peripheral expansion (17,18). Keratinocyte growth factor (KGF) stimulates expansion of the thymic epithelium, allowing for an increase in ETPs and thymic enlargement (15,19). The ablation of gonadal hormones increases chemokine ligand 25 (CCL25) and has similar overall effects (20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood

Gui¹,

Morales²,

Maxey³

et al. 2011

International Immunology

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Increasing the pool of cells at early T-cell developmental stages enhances thymopoiesis and is especially beneficial when T-cell production is compromised by radiation or aging. Within the immature double-negative (DN; CD4(-)CD8(-)) thymocyte subpopulation, the DN1 subset contains the most primitive cells including the rare early T-cell progenitors (ETPs). In the present study, a human MCL1 transgene, under the control of its endogenous promoter, resulted in enlargement of an undistorted thymus in C57/BL6 mice. Enlargement occurred in females but not males, being seen at 1 month of age and maintained during progression into adulthood as the thymus underwent involution. The small DN1 subset was expanded disproportionally (ETPs increasing from ∼0.016 to 0.03% of thymocytes), while more mature thymocytes were increased proportionally (1.5-fold) along with the stroma. DN1 cells from transgenic females exhibited increased viability with maintained proliferation, and their survival in primary culture was extended. Exposure of transgenic females to γ-irradiation also revealed an expanded pool of radioresistant DN1 cells exhibiting increased viability. While the viability of DN1 cells from transgenic males was equivalent to that of their non-transgenic counterparts directly after harvest, it was enhanced in culture-suggesting that the effect of the transgene was suppressed in the in vivo environment of the male. Viability was increased in ETPs from transgenic females, but unchanged in more mature thymocytes, indicating that primitive cells were affected selectively. The MCL1 transgene thus increases the viability and pool size of primitive ETP/DN1 cells, promoting thymopoiesis and radioresistance in peripubescent females and into adulthood.

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“…8 KGF has been shown to increase intrathymic levels of interleukin-7 (IL-7) and appears to act at least partially via IL-7 signaling. 9,10 When given to mice undergoing allogeneic bone marrow transplantation (allo-BMT), KGF preserves thymic architecture and improves thymocyte counts. 10 This benefit also has been demonstrated in middle-aged mice 4 and mice with active graftversus-host disease (GVHD).…”

Section: Introductionmentioning

confidence: 99%

Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

Jenq¹,

King²,

Volk

et al. 2009

Blood

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Thymic stromal lymphopoietin is not necessary or sufficient to mediate the thymopoietic effects of keratinocyte growth factor

Cited by 4 publications

References 10 publications

A novel approach to improve immune effector responses post transplant by restoration of CCL21 expression

A novel approach to improve immune effector responses post transplant by restoration of CCL21 expression

MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood

Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

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