What can be done to prevent graft versus host disease?

Waldmann, Herman; Cobbold, Stephen; Hale, Geoff

doi:10.1016/0952-7915(94)90084-1

Cited by 16 publications

(4 citation statements)

References 42 publications

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“…GvHD is the leading problem associated with allogeneic BMT and PB stem cell transplantation caused by transfusion of alloreactive host T cells into the recipient (79,80). The relatively low incidence and mildness of GvHD following CB transplants have triggered studies aimed at exploring the in vitro immune reactivity of CB cells (25,79,81).…”

Section: Discussionmentioning

confidence: 99%

“…The relatively low incidence and mildness of GvHD following CB transplants have triggered studies aimed at exploring the in vitro immune reactivity of CB cells (25,79,81). Preliminary data suggest that CB cells because of their relative immaturity are less alloreactive than BM cells, which could allow for more HLA mismatching between donor and recipient than is usually acceptable for transplant of blood or marrow hematopoietic stem cells from adults (6,17,79,82,83). Our results confirm that CB contains fewer T cells than normal PB and BM and does not differentiate into mature T cells during ex vivo expansion (84±86).…”

Section: Discussionmentioning

confidence: 99%

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Fetal Cord Blood as an Alternative Source of Hematopoietic Progenitor Cells: Immunophenotype, Maternal Cell Contamination, and Ex Vivo Expansion

Engel¹,

Kaya²,

Bald³

et al. 1999

Journal of Hematotherapy

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The present study was performed to investigate the character of hematopoietic progenitor cells in fetal cord blood (CB). Thirty blood samples from fetuses at a median of 24 weeks of gestation (range 19-29) and 30 neonatal CB samples were analyzed for their immunophenotype by three-color flow cytometry and examined for the presence of female cells by fluorescence in situ hybridization (FISH). We tested the effects of different cytokine combinations (rhIL-1beta, rhIL-3, rhIL-6, rh erythropoietin [rhEPO], rhGM-CSF plus rhSCF, and rhSCF plus rhflt3-ligand) on the differentiation of 100 CD34+-enriched neonatal CB cells for up to 21 days. Ex vivo expansion of 32 unselected fetal blood samples cells was performed in the presence of rhSCF and rhflt3-ligand. The percentage of CD34+ cells in fetal blood was significantly higher compared with neonatal CB (1.24%+/-0.82% versus 0.33%+/-0.18%, p = 0.0001) and inversely correlated with the age of gestation. The contamination of fetal and neonatal CB with maternal cells was low (1.72%+/-0.89%, range 1.0%-4.0%). By using rhflt3-ligand we were able to expand committed progenitor cells while maintaining cells with stem cell function. The use of expanded fetal immature progenitors might have implications for in utero transplantation and autologous gene therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fetal Cord Blood as an Alternative Source of Hematopoietic Progenitor Cells: Immunophenotype, Maternal Cell Contamination, and Ex Vivo Expansion

Engel¹,

Kaya²,

Bald³

et al. 1999

Journal of Hematotherapy

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“…However, donor lymphocytes present in the transplanted marrow can react against HLA antigens (and minor histocompatibility antigens, discussed later) present on the patient’s cells, resulting in an immune assault on the host tissue leading to graft versus host disease (GVHD) which can often, unfortunately, be fatal (Wingard et al , 1989). T‐cell depletion of the marrow prior to transplantation has been employed to reduce GVHD (Goldman et al , 1988; Hale & Waldmann, 1994; Waldmann et al , 1994). However, the absence of donor T cells is also associated, by an as yet undefined mechanism, with an increase in disease relapse.…”

Section: Introductionmentioning

confidence: 99%

Molecular matching in allogeneic bone marrow transplantation

Little

Madrigal

1999

European Journal of Immunogenetics

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“…In transplantation, these TCRs are generally directed against allogeneic major histocompatibility complex (MHC) or syngeneic MHC coupled with minor histocompatability antigens. 14,15 To specifically redirect RMTCs against pathologic class I MHC-restricted T lymphocytes in murine models of transplantation, we developed chimeric receptors that include the class I MHC K b molecule extracellular and transmembrane domains linked to either a murine or CD28-signaling tail. 10 The K b extracellular region serves as bait for K b -restricted pathologic T cells, whereas the signaling domain activates the RMTCs, inducing effector functions.…”

mentioning

confidence: 99%

Identification of a murine CD28 dileucine motif that suppresses single-chain chimeric T-cell receptor expression and function

Nguyen

Moisini

Geiger

2003

Blood

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Recent preclinical and clinical trials have demonstrated the therapeutic potential of T lymphocytes redirected with genetically engineered T-cell receptor (TCR) surrogates against infected, cancerous, or autoreactive cells. These surrogate TCRs link a ligand-recognition domain to signaling regions from the TCR. We previously compared the function of surrogate TCRs that include TCR or TCR and CD28 signaling regions. We found that primary murine T cells modified to specifically target K b -restricted CD8 ؉ T cells using either K b -or K b -CD28-receptors had similar functional activities, although the CD28-receptor showed a 2-fold to 4-fold decreased expression. We have now identified a previously unrecognized dileucine motif in the murine CD28 signaling domain that accounts for this reduced expression. Inactivation of this motif increased chimeric receptor surface expression 2-to 5-fold. T cells expressing the dileucinemutated CD28-chimeric receptor demonstrated enhanced proliferation, cytokine production, and cytolytic activities. Further, cells expressing this dileucine-mutated receptor were highly effective in eliminating antigen-specific CD8 ؉ T lymphocytes in vivo. These results therefore identify a critical motif limiting the function of receptor-modified T lymphocytes, demonstrate that inactivation of this motif enhances chimeric receptor function, and illustrate a potential novel application of receptor-modified T lymphocytes in the induction of immune tolerance. IntroductionT cells transgenically modified to express genetically engineered chimeric receptors (receptor-modified T cells [RMTCs]) can target antigens not normally recognized by the immune system. [1][2][3] The chimeric receptors that redirect these RMTCs against their targets functionally substitute for the T-cell receptor (TCR). They recognize target antigen through an extracellular antigen-recognition domain, such as a single-chain Fv fragment, and signal the RMTCs through a linked TCR-derived signal transduction domain, typically from the TCR chain. RMTCs have shown therapeutic potency in model systems, selectively targeting cancerous, infected, and autoreactive T cells, and have not shown significant toxicity in phase 1 clinical trials. [4][5][6][7] Although engineered surrogate receptors can redirect therapeutic T cells, their effectiveness in doing this may be limited by the limited signal they can transduce. Coreceptor and costimulatory signals, normally provided to T cells when they interact with a "professional" antigen-presenting cell, will often not be available to RMTCs engaging a ligand on a tumor or other target cell with a chimeric receptor. 8,9 These signals can promote T-cell survival, proliferation, and effector function and may therefore be critical for RMTC function. To overcome this limitation, we and others have developed single-chain chimeric receptors that incorporate modular signal transduction subunits derived from the TCR, costimulatory, and/or coreceptor molecules. 5,10-13 The receptor structure most commonly analy...

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What can be done to prevent graft versus host disease?

Cited by 16 publications

References 42 publications

Fetal Cord Blood as an Alternative Source of Hematopoietic Progenitor Cells: Immunophenotype, Maternal Cell Contamination, and Ex Vivo Expansion

Fetal Cord Blood as an Alternative Source of Hematopoietic Progenitor Cells: Immunophenotype, Maternal Cell Contamination, and Ex Vivo Expansion

Molecular matching in allogeneic bone marrow transplantation

Identification of a murine CD28 dileucine motif that suppresses single-chain chimeric T-cell receptor expression and function

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