Depletion of donor-reactive cells as a new concept for improvement of mismatched bone marrow engraftment using reduced-intensity conditioning

Prigozhina, Tatyana B.; Elkin, Gregory; Khitrin, Sofia; Slavin, Shimon

doi:10.1016/j.exphem.2004.07.017

Cited by 12 publications

(9 citation statements)

References 49 publications

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“…More subtle approaches to selective depletion of alloreactive T cells with preservation of graft-facilitating activity are clearly desirable. One such approach involves selective depletion of alloreactive T cells by presensitization of the graft to host antigens in mixed cultures in the presence of pro-apoptotic signals ex vivo [8][9][10][11][12][13] and in vivo [14]. The ex vivo procedure involves 3 to 7 days of incubation for specific sensitization of T cells by several rounds of antigen engagement, a state that concurrently increases their sensitivity to activation-induced cell death (AICD) [15,16].…”

Section: Introductionmentioning

confidence: 99%

Depletion of Naïve Lymphocytes with Fas Ligand Ex Vivo Prevents Graft-versus-Host Disease without Impairing T Cell Support of Engraftment or Graft-versus-Tumor Activity

Askenasy

Mizrahi

Ash

et al. 2013

Biology of Blood and Marrow Transplantation

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Graft-versus-host disease (GVHD) can be prevented by Fas-mediated selective depletion of host-sensitized donor lymphocytes ex vivo. We tested the hypothesis that Fas-mediated depletion of lymphocytes in the absence of host-specific antigenic stimulation can alleviate GVHD. Brief exposure (24 hours) of unstimulated donor lymphocytes to Fas ligand (FasL) ex vivo results in balanced apoptosis of CD8(+) and CD4(+) subsets with preferential depletion of CD62L and CD69, increased T regulatory fractions, and sustained responses to stimulation. This procedure ameliorates weight loss and improves the clinical and histologic score of skin and gastrointestinal GVHD with and without concurrent transplantation of hematopoietic progenitors and irrespective of conditioning-induced tissue injury. Although FasL-resistant donor T cells are less potent effectors of GVHD, they facilitate hematopoietic progenitor engraftment when infused with or after the graft and retain the potential to elaborate graft-versus-tumor reactions. These findings in a preclinical model together with the known trophic effects of FasL on primitive hematopoietic progenitors suggest that brief ex vivo incubation of hematopoietic grafts with FasL may improve the outcome and safety of clinical T cell-replete allogeneic and haploidentical transplants.

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Section: Introductionmentioning

confidence: 99%

Depletion of Naïve Lymphocytes with Fas Ligand Ex Vivo Prevents Graft-versus-Host Disease without Impairing T Cell Support of Engraftment or Graft-versus-Tumor Activity

Askenasy

Mizrahi

Ash

et al. 2013

Biology of Blood and Marrow Transplantation

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“…In some experiments (Fig. 1a), we have used the selective depletion of activated donor‐reactive host cells method [9], initiated a day after 5 Gy TBI. In this method described by Prigozhina et al.…”

Section: Methodsmentioning

confidence: 99%

“…, the recipient is exposed to donor bone marrow cells (20–30 × 10 6 ) for 1 day. A day following the injection of the bone marrow cells, IP 200 mg/kg Cy is given to the recipient, thus killing most of the proliferating recipient cells that responded to the donor cells in attempt to reject them [9]. This was followed a day later by grafts from 1 or 2 donors (again 20–30 × 10 6 ).…”

Section: Methodsmentioning

confidence: 99%

Multidonor bone marrow transplantation improves donor engraftment and increases the graft versus tumor effect while decreasing graft-versus-host disease

Zhanna

Hirshfeld

Weiss

et al. 2010

Transplant International

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Summary In partially matched donor transplantation, mandatory T‐cell depletion (TCD) increases the risks of rejection/graft failure, relapse, and post‐transplant infections. A multi‐donor approach was offered to resolve some of these drawbacks. This hypothesis was previously tested in a TCD fully mismatched murine model. However, the effect of multi‐donor transplantation (MDT) on graft‐versus‐host disease (GVHD) and graft versus tumor (GVT) effect were never tested. To assess the safety and efficacy of MDT, we used it in non‐TCD transplantation and murine breast carcinoma model. We found that when transplanting non‐TCD MDT composed by C57Bl/6 and C3H cells into BALB/c, a consistent trichimerism is established, dominated by C57Bl/6 cells. Following MDT the study animals experienced reduced GVHD compare with those transplanted from C57Bl/6 alone, while the GVT effect was superior. We conclude that MDT may serve as a technique that suppresses GVHD while maintaining the GVT effect.

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“…This strategy aims to gain the benefits of safer and more effective treatment of autoimmune disease as well as organ and allogeneic hematopoietic SCT while avoiding the detrimental circumstances of GVHD, infectious diseases and development of late malignant disorder. The concept of selective elimination of alloreactive T cells focusing on prevention of GVHD in the setting of allo-SCT has been tested by us and others previously, in various experimental models in vivo [7][8][9] as well as in an ex-vivo set-up using allogeneic priming in MLCs with or without extrication of the unwanted activated T cells. [10][11][12][13][14] The alloreactive T cells were sorted by means of (a) photosensitizing drugs, which can be preferentially incorporated and retained in activated T cells as opposed to resting T cells, 15,16 (b) specific monoclonal antibodies directed against activation markers such as CD25, CD69, CD40L, CD134 and CD137 that are differentially expressed on activated T cells [17][18][19][20][21][22][23][24] or (c) via activation-induced cell-mediated death by the CD95/ CD95L complex.…”

Section: Introductionmentioning

confidence: 99%

Selective elimination of alloreactivity in vitro and in vivo while sparing other T-cell-mediated immune responses

Morecki¹,

Gelfand²,

Yacovlev³

et al. 2011

Bone Marrow Transplant

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Selective elimination of alloreactive cells was carried out in the set-up of T-cell-mediated immunotherapy in an effort to gain the benefits of hematopoietic allogeneic transplantation while reducing the risk of GVHD. Low MW chemical compounds were screened for their effect on T-cell-mediated immune responses of murine-and human-derived lymphocytes. Selected compounds were further tested in secondary MLR assays in which sensitization to alloantigens was carried out in vitro, in the presence or absence of a given compound, followed by exposure to related and unrelated alloantigens or T-cell mitogenic stimulation. At a low concentration of o1 lM, a quinazoline derivative named AO#349 [2-(3,4,5-trimethoxyphenyl)-N-p-tolylquinazolin-4-amine], was able to induce 78-90% inhibition of a selective allogeneic response while retaining 492% immune reactivity to unrelated alloantigens and mitogenic stimuli in vitro. Following allogeneic sensitization in the presence of AO#349, elimination of alloreactivity to the priming alloantigens was also proved in a murine model of GVHD: 10 out of 15 sub-lethally irradiated mice inoculated with these sensitized cells were GVHD-free for 4200 days. AO#349 was efficient in induction of a selective elimination of alloreactivity and should be considered for clinical application in allogeneic cell-mediated immunotherapy.

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Depletion of donor-reactive cells as a new concept for improvement of mismatched bone marrow engraftment using reduced-intensity conditioning

Cited by 12 publications

References 49 publications

Depletion of Naïve Lymphocytes with Fas Ligand Ex Vivo Prevents Graft-versus-Host Disease without Impairing T Cell Support of Engraftment or Graft-versus-Tumor Activity

Depletion of Naïve Lymphocytes with Fas Ligand Ex Vivo Prevents Graft-versus-Host Disease without Impairing T Cell Support of Engraftment or Graft-versus-Tumor Activity

Multidonor bone marrow transplantation improves donor engraftment and increases the graft versus tumor effect while decreasing graft-versus-host disease

Selective elimination of alloreactivity in vitro and in vivo while sparing other T-cell-mediated immune responses

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