Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99

Antoine, Corinne; Müller, Susanna; Cant, Andrew J.; Cavazzana, Marina; Veys, Paul; Vossen, Jaak M.; Fasth, Anders; Heilmann, Carsten; Wulffraat, N. M.; Seger, Reinhard; Blanche, Stéphane; Friedrich, Wilhelm; Abinun, Mario; Davies, Graham; Bredius, Robbert G. M.; Schulz, Ansgar; Landais, Paul; Fischer, Alain

doi:10.1016/s0140-6736(03)12513-5

Cited by 521 publications

(453 citation statements)

References 14 publications

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“…2 Compiled experience of BMT for SCID from Europe revealed that in 294 recipients of MMRD BMT, 3-year survival was only 54%. 3 Furthermore, in another study, careful analysis of survival, according to the degree of HLA identity, showed that frank haploidentical (half-matched) transplantation resulted in only 25-30% long-term survival in patients with primary immunodeficiency. 4 This low success rate may reflect the intense T-cell depletion required to prevent GVHD, which contributes to slower immune reconstitution with prolonged periods of increased susceptibility to infections.…”

Section: Introductionmentioning

confidence: 99%

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

Roifman

Somech

Grunebaum

2008

Bone Marrow Transplant

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Little information is currently available on the outcome and the long-term restoration of immune function in infants with combined immunodeficiency and residual T cells (T þ CID) treated by BMT. We prospectively followed patients with T þ CID who received matched unrelated donor BMT at our center. Engraftment, immune reconstitution and transplant-related complications were recorded. Humoral and cellular immunity were evaluated. Ten patients with combined immune deficiency who had more than 1000 circulating T cells/ll were designated as having T þ CID. They were diagnosed at a mean age of 9.7 months and received a matched unrelated donor BMT at the mean age of 17.4 months. All 10 patients are alive and well at a mean of 110 months after transplant. All patients have evidence of full hemopoietic engraftment and robust immune function. We have shown here that matched unrelated donor BMT is highly effective in curing patients with T þ CID. This mode of treatment should be preferred for patients with T þ CID when a related identical donor is not available.

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Section: Introductionmentioning

confidence: 99%

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

Roifman

Somech

Grunebaum

2008

Bone Marrow Transplant

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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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“…14 In patients with RS defects, increased susceptibility to DNA damage in somatic and hematopoietic cells may significantly affect treatment response and prognosis. Hematopoietic stem cell transplantation (HSCT), a curative treatment for patients with SCID or CID, 15 may be preceded by conditioning regimens of radiomimetic drugs, such as cyclophosphamide, melphalan, busulfan, and thiotepa. 16,17 Also, transplantation may be followed by prophylaxis of graft-versus-host disease using agents that also have the potential to induce DNA DSBs.…”

mentioning

confidence: 99%

“…19,20 The survival rate after HSCT for RS-SCID or RS-CID has been reported to be lower in comparison to those with other genetic types of SCID and CID. 15,21 The impact of these newer pre-and posttransplantation regimens on survival rates relative to noneRS-SCID and noneRS-CID needs further evaluation. Furthermore, although HSCT treats these patients' immunodeficiency, these patients' somatic cells retain their DNA-repair defects and susceptibility to malignant transformation.…”

mentioning

confidence: 99%

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Lobachevsky

Woodbine

Hsiao

et al. 2015

The Journal of Molecular Diagnostics

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Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of g histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects. Severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) are rare genetic disorders. The incidence of SCID in Australia is 1 in 69,000 live births, 1 comparable to the reported incidence of 1 in 100,000 births worldwide. CID patients have increased susceptibility to invasive and opportunistic bacterial, viral, and fungal infections due to poor T-lymphocyte production and/or function, in addition to failure of B lymphocytes to generate functional antibodies. SCID is the extreme form of CID. Patients with this condition often present in the first year of life, with severe life-threatening infections, and consequently failure to thrive, requiring prompt intervention. SCID without treatment is usually fatal within the first year of life. 2 Both SCID and CID are genetically diverse syndromes, and over 50 molecular defects resulting in these syndromes have been described. 3 Approximately 30% of SCID patients have defects in V(D)J recombination (antigen receptor

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Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99

Cited by 521 publications

References 14 publications

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

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

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

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