Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adoptive immunotherapy in form of donor leukocyte infusions is effective in a significant number of patients with chronic myeloid leukemia (CML) that have relapsed after allogeneic bone marrow transplantation (BMT). However, the therapy is associated with clinically significant side effects such as graft-versus-host disease (GVHD) and bone marrow (BM) hypoplasia that may be avoided through the administration of T cells with specific antileukemic activity. Dendritic cells (DC) functioning as potent antigen presenting cells (APC) may play an important role in the generation of T cells with specificity against CML. We examined a subpopulation of CD1a+/CD14- DC generated in vitro from BM of normal subjects and patients with CML using granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4). These DC derived from both the BM of normal subjects and of patients with CML, differentiated and matured in culture in a similar way. However, DC derived from patients with CML, displayed decreased activity when tested with allogeneic T cells in a mixed lymphocyte reaction (MLR). Addition of interferon-alpha (IFN-alpha) to DC cultures significantly upregulated the expression of major histocompatibility complex (MHC) molecules (class I and class II) and costimulatory molecules (B7.1 and B7.2) on DC from normal donors and CML patients. However, DC grown from CML patients required a higher concentration of IFN-alpha. IFN-alpha also significantly improved the capacity of CML DC to stimulate T-lymphocyte responses. Fluorescence in situ hybridization (FISH) showed that only some CD1a+/CD14- DC derived from BM of patients with CML expressed the bcr/abl fusion gene. Incubation with INF-alpha decreased the proportion of bcr/abl positive DC.
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PMID:Clonal heterogeneity of dendritic cells derived from patients with chronic myeloid leukemia and enhancement of their T-cells stimulatory activity by IFN-alpha. 1039 Jan 93

In utero hematopoietic stem cell transplantation (IUT) results in limited chimerism and tolerance to alloantigens. We studied the relative role of B7.1 and B7.2 expression by dendritic cells (DCs) in engraftment and in generating donor-specific tolerance in fetal mice. Mature dendritic cells (mDCs) from B7.1(-/-) or B7.2(-/-) donors and wild-type (WT) lineage-depleted (lin(-)) C57BL/6 (B6) bone marrow (BM) were injected into BALB/c fetuses. Six weeks after IUT, B7.1(-/-) recipients had multilineage engraftment (4.7% +/- 0.8% T cells and 5.7% +/- 1.1% granulocytes) associated with graft-versus-host disease (GVHD) and decreased survival, but by 12 weeks only donor CD3(+) cells (2.1% +/- 1.3%) were present. Recipients of B7.2(-/-) mDCs and lin(-) WT B6 BM had exclusively CD3(+)CD4(+) T cells (11.8% +/- 8.5% at 6 weeks and 6.5% +/- 2.5% at 12 weeks). Most of the cells were T-helper 2, although 10.4% +/- 1.4% were of the T-regulatory (T(reg)) phenotype, ie, CD4(+)CD25(+). Donor T(reg) cells were detected both in the thymus and spleen, thus suggesting an effect on both central and peripheral immunity. The animals with T(reg) cells had better survival (82.3% versus 47.4%; P < .01) and no GVHD (0% versus 65%; P < .001). This group alone demonstrated multilineage engraftment of donor hematopoietic cells after postnatal transplantation with megadoses of donor lin(-) BM. Both the engrafted donor CD4(+)CD25(-) and CD4(+)CD25(+) cells induced comparable in vitro suppression of T-cell proliferation, thus suggesting their role in the persistence of the donor T cells in vivo. The CD4(+)CD25(-) cells produced interleukin 10 or interleukin 4 and were inhibited by anti-T-helper 2 cytokine-neutralizing antibodies, whereas the CD4(+)CD25(+) cells showed no evidence of any involvement of a cytokine-like soluble mediator and expressed cytotoxic T-lymphocyte antigen 4 (CTLA-4) and foxp3 constitutively. Donor mDCs and donor CD4 T cells were detected among the thymocytes of the recipients of B7.2(-/-) mDCs and lin(-) WT B6 BM. Thus, it seems that costimulatory molecule expression of donor DCs can play a significant immunomodulatory role in survival, GVHD, engraftment, and homing of allogeneic BM cells after IUT through the generation of T(reg) cells.
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PMID:B7.2-/- mature dendritic cells generate T-helper 2 and regulatory T donor cells in fetal mice after in utero allogeneic bone marrow transplantation. 1612 36