Selective Cd4+ T-Cell Depletion Does Not Prevent Graft-Versus-Host Disease1

Nagler, Arnon; Condiotti, Reba; Nabet, Corinne; Naparstek, E; Or, Reuven; Samuel, Simcha; Slavin, Shimon

doi:10.1097/00007890-199807150-00025

Cited by 21 publications

(8 citation statements)

References 8 publications

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“…Moreover, donor lymphocyte infusions depleted of CD8+ cells induce remissions of relapsed chronic myelogenous leukemia, with a low rate of severe aGvHD, supporting the hypothesis that CD8+ lymphocytes are important effectors of aGvHD [20]. In contrast, HLA-matched BMT depleted of CD4+ cells did not prevent aGvHD [21]. …”

Section: Discussionmentioning

confidence: 78%

CD8+ Lymphocytes in the Blister Fluid of Severe Acute Cutaneous Graft-versus-Host Disease: Further Similarities with Toxic Epidermal Necrolysis

et al. 2001

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Background: Graft-versus-host disease (GvHD) remains the major toxicity of allogeneic bone marrow transplantation (BMT). In the acute form of the disease, the differential diagnosis includes viral rash and drug eruptions. Methods: We report two patients with chronic myeloid leukemia submitted to allogeneic BMT who developed a severe form of acute cutaneous GvHD, with clinical and histological pictures mimicking toxic epidermal necrolysis (TEN). Results: We found a predominance of peripheral CD8+ T lymphocytes and, at the same time, studying the cellular profile of the blister fluid, just in the beginning of blister eruption, we also found a high proportion of CD8+ T lymphocytes, mainly CD8+CD57–. Conclusion: These data are in agreement with previous reports of the presence of CD8+ T cells in the blister fluid of patients with TEN, further emphasizing similar immunoinflammatory pathways in both diseases.

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Section: Discussionmentioning

confidence: 78%

CD8+ Lymphocytes in the Blister Fluid of Severe Acute Cutaneous Graft-versus-Host Disease: Further Similarities with Toxic Epidermal Necrolysis

et al. 2001

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“…Conflicting data have been reported on whether T-cell depletion reduces the incidence of GVHD [17,[22][23][24]. However, infusing < 10 5 T cells/kg is considered necessary to avoid significant GVHD in fully HLA-matched unrelated transplants; 3 ×10…”

Section: Discussionmentioning

confidence: 99%

Selection of CD34-Positive Blood Cells for Allogeneic Transplantation: Approaches to Optimize D34-Cell Recovery, Purity, Viability, and T-cell Depletion

Fritsch¹,

Scharner²,

Fröschl³

et al. 2000

Oncol Res Treat

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Background: Methods for clinical-scale selection of CD34-positive hematopoietic stem and progenitor cells have facilitated allogeneic transplants using HLA-mismatched healthy donors. We examined different approaches to purify mobilized CD34+ cells, focusing on yield, purity, and viability of the selected cells and T-cell depletion levels. Methods: Sixty-seven CD34-positive selections were performed for a total of 37 allogeneic transplantations, 23 of which from HLA-haploidentical donors. The selection devices were the Isolex^® 300i (v. 1.12) used alone (n =13) or with the SuperMACS (n = 29); the CliniMACS (n = 3); and the Isolex 300i (v. 2.0b1). The latter was used for CD34-positive selection (n = 7) and combined CD34+/CD4 8 19-negative selections (n =15). DNAse was included to reduce cell clumping. Results: With the Isolex 300i (v. 1.12), the median CD34+-cell recovery increased from 51% (without DNAse) to 61% (15 mg DNAse) and 70% (7.5 mg). DNAse (5 mg) was used for 22 selections with the Isolex (v. 2.0b1) without cell clumping. CD34-positive cell purity, yield, and viability, as well as the degree of CD3 depletion varied with the selection device and procedure used. Conclusion: With regard to all of the above-mentioned parameters, the best results were obtained with the Isolex 300i (v. 2.0b1). Values achieved for CD34-positive cells were 98% for purity, 50–60% for yield, and > 96% for cell viability; T-cell depletion was 4.5 to > 5 log. The automated and closed system provides target cells that are free of both magnetic particles and murine monoclonal antibody.

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“…In addition, when CD4 and CD8 T-cell populations were examined separately, no difference was found in the killing efficiency or in the IC 50 value (data not shown). This information is relevant because CD4 and CD8 donor lymphocytes contribute to GVHD, as shown by donor lymphocyte infusion protocols involving the infusion of either CD4-depleted 20 or CD8-depleted donor lymphocytes. 21 LVЈVFas-transduced T lymphocytes demonstrated normal viability in the absence of drug, indicating the absence of autotoxicity-signaling in the absence of added drug (data not shown).…”

Section: Lvvfas Transgene Confers Susceptibility To Ap1903-induced Cementioning

confidence: 99%

A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease

Thomis

Marktel

Bonini

et al. 2001

Blood

177

124

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Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. One strategy to treat GVHD is to equip donor T cells with a conditional suicide mechanism that can be triggered when GVHD occurs. The herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir system used clinically has several limitations, including immunogenicity and cell cycle dependence. An alternative switch based on chemically inducible apoptosis was designed and evaluated. A chimeric human protein was expressed comprising an extracellular marker (⌬LNGFR), the Fas intracellular domain, and 2 copies of an FK506-binding protein (FKBP). Primary human T lymphocytes retrovirally transduced with this construct could be purified to homogeneity using immunomagnetic beads. Genetic integrity of the construct was ensured by redesigning repetitive sequences. Transduced T cells behaved indistinguishably from untransduced cells, retaining the ability to mount a specific antiallogeneic immune response. However, they rapidly underwent apoptosis with the addition of subnanomolar concentrations of AP1903, a bivalent "dimerizer" drug that binds FKBP and induces Fas cross-linking. A single 2-hour treatment eliminated approximately 80% of T cells, and multiple exposures induced further apoptosis. T cells were eliminated regardless of their proliferation state, suggesting that the AP1903/ Fas system, which contains only human components, is a promising alternative to HSV-tk for treating GVHD. IntroductionIn allogeneic bone marrow transplantation (BMT), the delayed infusion of donor lymphocytes plays a central therapeutic role in the control of disease relapse (graft-versus-leukemia effect [GVL]) 1 and in the induction of immune reconstitution, 2,3 the latter especially in the subset of T-depleted matched transplants and in the context of partially mismatched transplants. 4 However, graft-versushost-disease (GVHD) represents a frequent and often lethal complication of delayed lymphocyte infusions. 1 Managing the threat of GVHD while maximizing the beneficial GVL effect would broaden the scope and usefulness of allogeneic BMT procedures.We and others have previously demonstrated that ex vivo genetic manipulation of donor lymphocytes to insert a conditional, drug-inducible suicide gene provides a means for the specific elimination of donor T cells with the onset of GVHD while maximizing the therapeutic benefit of the GVL effect. 2,5,6 Although a number of suicide genes have been proposed, 7,8 the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV)-based suicide strategy appears to be the most effective and specific and has been widely adopted. 9,10 Cells are engineered to express HSV-tk; the addition of ganciclovir leads to cell death through tk-catalyzed metabolism of the drug to a lethal product. In the current clinical trial, 6 HSV-tk-engineered-donor T cells demonstrated an effective antileukemic effect, and GVHD could be successfully treated through GCV administration. 2,11 Despite this demonstration of efficacy, ...

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Selective Cd4+ T-Cell Depletion Does Not Prevent Graft-Versus-Host Disease1

Cited by 21 publications

References 8 publications

CD8+ Lymphocytes in the Blister Fluid of Severe Acute Cutaneous Graft-versus-Host Disease: Further Similarities with Toxic Epidermal Necrolysis

CD8+ Lymphocytes in the Blister Fluid of Severe Acute Cutaneous Graft-versus-Host Disease: Further Similarities with Toxic Epidermal Necrolysis

Selection of CD34-Positive Blood Cells for Allogeneic Transplantation: Approaches to Optimize D34-Cell Recovery, Purity, Viability, and T-cell Depletion

A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease

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