Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The products of the human ARG gene and the human ABL gene characterize the Abelson family of non-receptor tyrosine protein kinases. Both genes are ubiquitously expressed. The interactions of these two similar protein kinases are still not well known, although it has been suggested that they could cooperate, with redundant actions, to provide intracellular signals in the cells. Lymphopenia occurs in mice with homozygous disruption of c-abl, indicating that in certain tissues Arg is unable to substitute c-abl functions. In B and T lymphoid cell lines at different stages of differentiation, we studied, by a reverse transcriptase-competitive polymerase chain reaction and Western blotting, Arg and c-abl in order to evaluate whether the expression pattern of the two genes could give insight as to why they do not exhibit overlapping roles in lymphocytes and whether the product levels of the two genes are related to lymphoid differentiation. The data showed that their expression is differently modified in lymphoid B cell lines. The highest Arg transcript and protein levels are in the mature B cells.
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PMID:The expression of the non-receptor tyrosine kinases Arg and c-abl is differently modulated in B lymphoid cells at different stages of differentiation. 1222 Jun 63

Allogeneic stem cell transplantation remains a curative treatment for haematological malignancies resistant to other treatment approaches through the unique graft-versus-leukaemia effect (GvL). However, the lack of specificity of this response results in the targeting of normal tissue, and the morbidity and mortality associated with graft-versus-host disease (GvHD). Further improvements in exploiting the GvL effect to prevent relapse in high-risk leukaemias while minimizing toxicity have focused on the use of targeted anti-leukaemic immunotherapy. These strategies include the use of vaccines against minor histocompatibility antigens (HA-1, HA-2 and H-Y) and leukaemia-specific antigens (proteinase 3, Wilms' tumour 1 and BCR-ABL), and the adoptive transfer of leukaemia-specific T cells. The unique post-transplant milieu, which is characterized by lymphopenia, regulatory T-cell depletion and the release of growth factors, offers the opportunity to promote the expansion of engrafted T cells and enhance the specific GvL response. Techniques to reduce regulatory T-cell control over T-cell responses to leukaemia antigens could further enhance GvL reactivity. Finally, these approaches to increase GvL effects would be facilitated by transplant approaches to deplete GvHD alloresponses selectively while preserving GvL reactivity.
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PMID:Characterizing and optimizing immune responses to leukaemia antigens after allogeneic stem cell transplantation. 1879 Apr 48

Allogeneic hematopoietic stem cell transplantation (allogeneic HSCT) remains a curative treatment for hematological malignancies resistant to other treatment approaches through the unique GVL effect. However, relapse remains a major cause of treatment failure after allogeneic HSCT for patients with high-risk hematological malignancies. Further improvements in exploiting the GVL effect to prevent relapse in high-risk leukemias while minimizing toxicity have focused on the use of targeted antileukemic immunotherapy. These strategies include methods to boost the GVL effect with leukemia vaccines or the adoptive transfer of leukemia-specific lymphocytes. Vaccines can be classified as those against defined antigens such as minor histocompatibility antigens (mHags) or leukemia-associated antigens (PR1, WT1, and BCR-ABL) and those that have broad "antileukemic" activity such as engineered irradiated leukemia cells or leukemia-derived dendritic cells (DCs). The unique posttransplantation milieu, which is characterized by lymphopenia, regulatory T-cell depletion, and the release of growth factors, provides a unique opportunity for effective antitumor immunotherapy and augmenting specific GVL responses. This review focuses on approaches to enhancimg the GVL response by combining allogeneic HSCT with vaccination.
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PMID:Posttransplantation vaccination: concepts today and on the horizon. 2216 49

PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30-120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compared with 2/5 BCR-ABL-positive patients (P = 0.025). In contrast, PR1 responses were detected in 2/4 MRD-negative compared with 4/5 MRD-positive ALL patients (P = 0.76). To assess whether the lymphopenic milieu also exaggerates weak T-cell responses in the autologous setting, we measured spontaneous induction of PR1 responses in 3 AML patients vaccinated with WT1-126 peptide following lymphodepletion. In addition to WT1-specific T cells, we detected PR1-specific T cells in 2 patients during hematopoietic recovery. Our findings suggest that lymphopenia induced by chemo-radiotherapy enhances weak autoimmune responses to self-antigens, which may result in GVL if the leukemia expresses the relevant self-antigen.
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PMID:Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy. 2219 10