Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure

Chen, Jichun; Lipovsky, Karen; Ellison, Felicia M.; Calado, Rodrigo T.; Young, Neal S.

doi:10.1182/blood-2004-03-1115

Cited by 75 publications

(82 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pancytopenia associated with hypoplastic bone marrow is often seen in GVHRs by the transfer of donor cells that contain few hematopoietic stem cells and in recipients that show little hostvs-graft reactivity (27,28). This model of GVHR closely resembles that of a study by Chen et al (26) in which parental lymph node cells were infused into sublethally irradiated F 1 recipients. Affected animals also developed a fatal pancytopenia along with bone marrow destruction within 2-3 wk, without the other typical signs of GVHD.…”

Section: Discussionmentioning

confidence: 65%

“…In this model, infusion of parental splenocytes into sublethally irradiated F 1 recipients resulted in a graft-vs-host reaction (GVHR) characterized by severe pancytopenia and which caused mortality of all recipient animals. Pancytopenia is one of the consequences of GVHR and is frequently observed after the injection of lymphoid cells in sublethally irradiated F 1 hybrid mice (26,27). Moreover, it is a commonly reported manifestation of transfusion-associated GVHD (28).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Verbinnen

Billiau²,

Vermeiren

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F1 offspring (C57BL/6 × C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25+ cell-depleted splenocyte transfer, showing that CD25+ natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6–30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3+ cells among donor CD4+ cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance.

show abstract

Section: Discussionmentioning

confidence: 65%

mentioning

confidence: 99%

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Verbinnen

Billiau²,

Vermeiren

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…This had been earlier demonstrated by Rozendaal et al 36 in the DBA/2-B6D2F1 model. In contrast, Chen et al 16,17 have shown in the C57BL/6-CByB6F1 model that the BM of F1 mice with BMGvHD not only fails to form stromal feeder layers in vitro, but also contains T cells capable of destroying fresh donor-type stem cells as well, indicating that in this model innocent bystander destruction of both stromal and hematopoietic progenitor cells is taking place. In contrast to these studies, the model we present here does not include irradiation, and inflammation may influence the degree to which bystander destruction is taking place.…”

Section: Discussionmentioning

confidence: 95%

“…Reportedly, highdose C57BL/6 splenocytes induce acute epithelial GvHD that is lethal over several months. 14 In contrast, high-dose C57BL/6 LN cells induces a BMGvHD, which is rapidly lethal; [15][16][17] BMGvHD is also seen if recipients are irradiated, in which case lower quantities of C57BL/6 T cells are required. Here, we found that challenge of B6DBA2F1 with C57BL/6 splenocytes gave rise to two distinct outcome patterns.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Earlier studies in the C57BL/6-B6DBA2F1 model showed that high-dose C57BL/6 splenocytes induce acute epithelial-tissue GvHD that is lethal over several months. 14 In contrast, high-dose C57BL/6 lymph node (LN) cells induces a BM failure type of GvHD (BMGvHD), which is rapidly lethal; [15][16][17] BMGvHD is also seen if recipients are irradiated, in which case lower quantities of C57BL/6 T cells are required. The characteristics of parent-in-F1 GvHD is equally known to vary between strain combinations, and to depend on strainspecific alloreactive T-cell-precursor frequency.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction

Sprangers

Wijmeersch

Luyckx

et al. 2010

Bone Marrow Transplant

View full text Add to dashboard Cite

GvHD is an important complication of allogeneic hematopoietic SCT. Parent-in-F1 models are frequently used to study GvHD immunobiology; the characteristics of parent-in-F1 GvHD vary between strain combinations and induction protocols. Here, we observed that a high-dose challenge of non-irradiated B6DBA2F1 and B6SJLF1 recipients with C57BL/6 splenocytes left the majority of recipients clinically healthy, while inducing progressive high-grade donor T-cell chimerism. We investigated this previously undescribed pattern of parent-in-F1 T-cell alloreactivity and studied the effect of serial parental splenocyte infusions on epithelial and lymphohematopoietic tissues. The majority of recipients of 4 weekly splenocyte infusions showed long-term survival with gradual establishment of high-grade donor chimerism and without any signs of epithelial-tissue GvHD. A minority of recipients showed BM failure type of GvHD and, respectively, graft rejection. Moreover, long-term F1 chimeras showed protracted pancytopenia, and in peripheral lymphoid tissues severe lymphopenia and near-complete eradication of APCs and dysfunction in antigen-presenting capacity in remaining APC. Hematopoiesis and lymphoid tissue composition recovered only after multilineage donor chimerism had established. In conclusion, we report on a novel type of parent-in-F1 hybrid GvHD, where a cumulative high dose of C57BL/6 parental splenocytes in non-irradiated F1 mice induces subclinical but severe hematolymphoid-tissue GvHD, causing prolonged immuno-incompetence.

show abstract

The effectiveness of a novel treatment of TIM‐3(−) NK cells infusion in murine models of immune‐mediated bone marrow failure

Ding

Zhang

Liu

et al. 2023

Clinical Laboratory Analysis

View full text Add to dashboard Cite

BackgroundT‐cell immunoglobulin and mucin‐containing domain (TIM)‐3 exerts its inhibitory effect on NK cells and participates in the immune pathogenesis of SAA. In this study, we aimed to explore a novel treatment method of TIM‐3(+) NK or TIM‐3(−) NK cell infusion in combination with immunosuppressive therapy for bone marrow failure (BMF)/aplastic anemia (AA) mice.MethodsBMF/AA mouse model was constructed. The TIM‐3 expression and functional molecules on TIM‐3(+) and TIM‐3(−) NK cells of the BMF group, total body irradiation (TBI) group, and normal control (NC) group mice were detected by flow cytometry. After treatment, the general condition, whole blood cell and bone marrow cell (BMC) count, and immune condition of mice from each group were compared.ResultsTIM‐3 expression in the peripheral blood NK cells of BMF mice was significantly lower than that of the TBI and NC group mice. TIM‐3(−) NK cells expressed more NKG2D receptors than TIM‐3(+) NK cells. The levels of P‐Akt and PI3K in TIM‐3(−) NK cells were higher than those in TIM‐3(+) NK cells. On the 17th day after BMF induction, the weight, peripheral whole blood cell count, and BMC count of BMF mice decreased significantly compared with that of the NC group mice. The therapeutic effect in the TIM‐3(−) NK cell treatment group was better than that in the TIM‐3(+) NK cell treatment and CsA treatment groups. Concurrently, the ratio of CD4+T and CD8+T cells of BMF mice was significantly lower than that of the NC group mice. The therapeutic effect in CsA + TIM‐3(−) NK group was more significant than that of the CsA treatment and the CsA + TIM‐3(+) NK groups.ConclusionsIn this study, we found that the general condition, peripheral whole blood cell and BMC count, and immune status of BMF mice improved significantly after CsA + TIM‐3(−) NK cell treatment. These results may provide further insights into the immune pathogenesis of SAA and novel therapeutic ideas for improving SAA treatment.

show abstract

Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure

Cited by 75 publications

References 28 publications

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction

The effectiveness of a novel treatment of TIM‐3(−) NK cells infusion in murine models of immune‐mediated bone marrow failure

Contact Info

Product

Resources

About