Immunoreconstitution in Severe Combined Immunodeficiency After Transplantation of Hla-Haploidentical, T-Cell-Depleted Bone Marrow

Friedrich, Wilhelm; Vetter, U.; B, Heymer; Reisner, Yaīr; Goldmann, S. F.; Fliedner, Theodor M.; Hh, Peter; Kleihauer, E.

doi:10.1016/s0140-6736(84)91277-7

Cited by 95 publications

(16 citation statements)

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“…Allogeneic hematopoietic stem cell transplants have the potential to play a significant curative role in the treatment of malignant and non-malignant hematopoietic disorders, autoimmune diseases, and immunological deficiencies, and in the induction of transplantation tolerance [1][2][3][4][5][6][7][8][9][10]. Widespread application of this therapeutic modality is limited due to the morbidity and mortality of graft versus host disease (GVHD), which affects 50% of stem cell transplant recipients [11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

et al. 2008

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Graft versus host disease (GVHD), mediated by donor T cells, is a significant source of morbidity and mortality following allogeneic stem cell transplantation. Mesenchymal stem cells (MSC) can successfully treat ongoing graft versus host disease, presumably due to their ability to suppress donor T cell proliferation. Little is known about the potential of MSC to prevent GVHD. Here we show that bone marrow-isolated MSC can suppress the development of GVHD if given after donor T cell recognition of antigen. IFN-c was required to initiate MSC efficacy. Recipients of IFN-c -/-T cells did not respond to MSC treatment and succumbed to GVHD. MSC, pre-treated with IFN-c, became immediately active and could suppress GVHD more efficiently than a fivefold-greater number of MSC that were not activated. When given at the time of bone marrow transplantation, activated MSC could prevent GVHD mortality (100% survival, p=0.006). MSC activation was dependent on the magnitude of IFN-c exposure, with increased IFN-c exposure leading to increased MSC suppression of GVHD. Activated MSC present a new strategy for preventing GVHD using fewer MSC. Key words: Mesenchymal stem cell Á GVH disease Á IFN-c See accompanying commentary by Dazzi and Marelli-Berg IntroductionAllogeneic hematopoietic stem cell transplants have the potential to play a significant curative role in the treatment of malignant and non-malignant hematopoietic disorders, autoimmune diseases, and immunological deficiencies, and in the induction of transplantation tolerance [1][2][3][4][5][6][7][8][9][10]. Widespread application of this therapeutic modality is limited due to the morbidity and mortality of graft versus host disease (GVHD), which affects 50% of stem cell transplant recipients [11][12][13][14][15][16]. While grafts highly matched to the recipient, young donors, donor/recipient sex match, and posttransplant immunosuppression are strategies used to reduce the risk of GVHD [17], thus far, the greatest preventative measure has been intentional underutilization of stem cell transplantation. Theoretically, strategies aimed at preventing GVHD would target early initiating factors either during the inflammatory milieu created in the wake of tissue damage from conditioning regimens [18,19] or during T cell antigen recognition and proliferation [20,21]. Once the efferent effector phase occurs, donor T cell-mediated destruction of host tissues occurs and preventive strategies are replaced with treatment regimens [19].Mesenchymal stem cells (MSC) have been used in the efferent phase of GVHD to successfully treat ongoing, acute, steroidresistant GVHD [22,23]. In contrast, when given at the time of BM transplant, for the prevention of GVHD, the incidence of grade III/ IV GVHD was not significantly improved [24], suggesting the [26,27,29,30]. In addition, MSC do not suppress the modest T cell proliferative response to recall antigens [31]. These findings suggest MSC may exert their optimal effects during the events surrounding larger scale T cell activation and proliferat...

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Section: Introductionmentioning

confidence: 99%

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

et al. 2008

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“…Transplants of marrow from haploidentical or fully mismatched donors regularly cause lethal graft-versus-host disease (1, 2). The successful use of T-cell-depleted haploidentical parental marrow for the transplantation of children with severe combined immune deficiency has shown that graft-versus-host disease can be prevented and should, therefore, no longer present a major obstacle in allogeneic transplantations (3)(4)(5)(6)(7). However, other problems were encountered when this approach was used for the treatment of patients with acute leukemia.…”

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confidence: 99%

Demonstration of clonable alloreactive host T cells in a primate model for bone marrow transplantation.

Reisner¹,

Ben‐Bassat²,

Douer³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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The phenomenon of marrow rejection following supralethal radiochemotherapy was explained in the past mainly by non-T-cell mechanisms known to be resistant to high-dose irradiation. In the present study a low but significant number of radiochemoresistant-clonable T cells was found in the peripheral blood and spleen of Rhesus monkeys following the cytoreductive protocol used for treatment of leukemia patients prior to bone marrow transplantation. More than 95% of the clonable cells are concentrated in the spleen 5 days after transplant. The cells possess immune memory as demonstrated by the generation of alloreactive-specific cytotoxicity. The present findings suggest that host-versus-graft activity may be mediated by alloreactive T cells. It is hoped that elimination of such cells prior to bone marrow transplantation will increase the engraftment rate of HLA-nonidentical marrow in leukemia patients. MATERIALS AND METHODSAnimals. Colony-born Rhesus monkeys aged 3-5 years were used. The five males weighed 8-11 kg each and the two females weighed 3 and 5 kg.Conditioning Regimen. The radiation and chemotherapy regimen was adapted from that developed for the conditioning of leukemia patients prior to bone marrow transplantation (9). Briefly, hyperfractionated total body irradiation, comprising 11 fractions of 120 cGy each delivered from a cobalt-60 source at a rate of 15 cGy/min three times per day on days -7 to -4, was given to the sedated monkeys without lung shielding. On days -3 and -2, cyclophosphamide (60 mg/kg) was administered intravenously. Four of the monkeys were sacrificed on day 0 (designated as the day when bone marrow transplantation would have been performed), and three monkeys were supported for 5 additional days and then sacrificed. The monkeys were kept in reverse isolation, fed sterile food, and given 100,000 units of nystatin and 40 mg of gentamycin sulfate orally three times daily. All procedures were performed after sedation with ketamine (10 mg/kg).Cell Preparation. Normal saline solution was perfused through the great vessels, and 600-1000 ml of the perfusate was collected. The spleen and accessible lymph nodes were dissected, and the cells were suspended in Mg2+/Ca2+-free phosphate-buffered saline, pH 7.4. The mononuclear cells were isolated by centrifugation on a Ficoll/Hypaque gradient. The E-rosette assay was performed as described (10). Isolation of T lymphocytes from the peripheral blood mononuclear cells was carried out by the E-rosetting technique using sheep erythrocytes as described (3).Limit Dilution Analysis for Clonable T Cells. The method of Chen et al. (11) The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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“…This delayed pattern of immune reconstitution is similarly observed in patients with primary immunodeficiencies, transplanted with T celldepleted HLA non-identical bone marrow, likely reflecting the time of thymus-dependent maturation of T cells from precursor cells. 27,28 In a group of adult patients, Albi et al 29 reported a similar rapid reconstitution of NK cells after HLA non-identical transplantation. T cell reconstitution however was more heterogenous and was dominated by the appearance of CD8 + cells.…”

Section: Discussionmentioning

confidence: 93%

Definition of a critical T cell threshold for prevention of GVHD after HLA non-identical PBPC transplantation in children

Muller

Schulz

Reiss

et al. 1999

Bone Marrow Transplant

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Summary:The aim of this study was to reduce the rate of graft failure after HLA non-identical stem cell transplantation by using G-CSF mobilized CD34 ؉ peripheral blood progenitor cells (PBPC), either in combination with bone marrow or as single grafts. To prevent GVHD, PBPC were highly purified, resulting in a 5 to 6 log T cell depletion. In additon to T cell depletion no further GVHD prophylaxis was used. We transplanted 23 pediatric patients with life-threatening malignant or non-malignant hematological disorders, who had no available matched donor. Engraftment was obtained in 18 of 21 evaluable patients. Five patients developed acute GVHD of grade II and III, which became chronic in four cases and was fatal in four. The use of highly purified PBPC allowed the exact quantification of residual T cells in the grafts and a strict correlation between the residual T cell load and the development of GVHD was observed: patients with GVHD had received numbers of T cells between 8 and 20 ؋ 10 4 /kg, whereas patients without GVHD were grafted with T cell numbers ranging from 0.7 to 6.0 ؋ 10 4 /kg. We therefore clearly demonstrate that a residual T cell content of Ͻ5 ؋ 10 4 /kg is safe for prevention of GVHD after HLA non-identical PBPC transplantation in children. Keywords: HLA non-identical transplantation; peripheral blood progenitor cells; grafted T cell number; GVHD HLA haplo-identical BMT with T cell depletion (TCD) has been used successfully to treat children with primary immunodeficiency disorders. [1][2][3] In patients with other diseases, this transplant approach has frequently failed because of graft rejection. [4][5][6] Graft failure may result from the profound T cell depletion required to prevent GVHD, with the ensuing loss of the graft-enhancing effect mediated by T cells. 7,8 More intensive immunosuppressive conditioning to counterbalance this disadvantage has usually had limited success because of significant complications from toxicity. Less vigorously T cell-depleted grafts carry the risk of severe GVHD. From animal models it is clear that engraftment may also be improved by increasing the number of grafted cells, either using unmanipulated bone marrow, taking advantage of the effect of alloreactive T cells or, as shown in recent studies, by using high numbers of highly purified T cell-depleted stem cells. 9 The latter approach was used by Aversa et al to transplant patients with leukemia from HLA non-identical family donors using either a combination of purified peripheral blood progenitor cells (PBPC) and T cell-depleted marrow or, in more recent patients, PBPC alone. 10-12 A remarkably high engraftment rate of more than 90% was observed.Here we report results of a pilot study in pediatric patients, where we explored a comparable transplant approach. Like the findings of Aversa et al, we observed a high engraftment rate of 86%. In contrast, GVHD developed in the initial patients, but was completely preventable in patients receiving grafts containing fewer T cells than 5 ϫ 10 4 /kg. Patients and meth...

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Immunoreconstitution in Severe Combined Immunodeficiency After Transplantation of Hla-Haploidentical, T-Cell-Depleted Bone Marrow

Cited by 95 publications

References 11 publications

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

Demonstration of clonable alloreactive host T cells in a primate model for bone marrow transplantation.

Definition of a critical T cell threshold for prevention of GVHD after HLA non-identical PBPC transplantation in children

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