Faculty Collaboration Database

Modulation of in vitro and in vivo T-cell responses by transferrin-gallium and gallium nitrate. Blood 1996 Oct 15;88(8):3056-64

Date

10/15/1996

Pubmed ID

8874204

DOI

10.1182/blood.v88.8.3056.bloodjournal8883056

Scopus ID

2-s2.0-0029859282 (requires institutional sign-in at Scopus site)   25 Citations

Abstract

Gallium is a group IIIa metal that has efficacy in the therapy of malignant disorders such as lymphoma and urothelial tract tumors. Preclinical studies also indicate a role for gallium in autoimmune disorders, suggesting that gallium is able to modulate T-cell immune reactivity. The purpose of this study was to examine the in vitro and in vivo immunomodulatory action of gallium on T-cell function. Since gallium binds to transferrin in vivo, in vitro studies evaluated the effect of transferrin-gallium (Tf-Ga) on human T cells. Tf-Ga inhibited the mitogen-induced proliferative response of peripheral blood mononuclear cells (PBMC) in a dose-dependent fashion. Alloantigen-induced proliferation was also potently suppressed when evaluated in a mixed lymphocyte culture assay. Tf-Ga affected a significant reduction in the density of IL-2 receptors on activated T cells and a slight reduction in the number of CD3+/CD25+ T cells in PHA-stimulated cultures. Neither secretion of interleukin-2 (IL-2) nor the induction of IL-2-stimulated lymphokine-activated killer activity, however, was inhibited by Tf-Ga. Tf-Ga produced significant upregulation of the transferrin receptor (CD71) in T cells as determined by flow cytometric analysis and northern blot assay, but did not affect the percentage of CD3+/ CD71+ T cells after mitogen stimulation. To assess the in vivo effects of gallium on alloreactive T cells, we evaluated the immunosuppressive effect of gallium in a murine model of graft-versus-host disease (GVHD). Administration of gallium significantly prolonged survival in mice undergoing severe GVHD, suggesting that gallium can ameliorate GVH reactivity. Collectively, these data demonstrate that, at clinically achievable concentrations, Tf-Ga potently inhibits T-cell activation and that this immunosuppressive property of gallium may be of adjunctive therapeutic value in the management of disorders characterized by the presence of autoreactive or alloreactive T-cell populations.

Author List

Drobyski WR, Ul-Haq R, Majewski D, Chitambar CR

Author

William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bone Marrow Transplantation
Drug Evaluation, Preclinical
Gallium
Graft vs Host Disease
Humans
Immunosuppressive Agents
Interleukin-2
Killer Cells, Lymphokine-Activated
Lymphocyte Activation
Mice
Mice, Inbred AKR
Radiation Chimera
Receptors, Transferrin
T-Lymphocyte Subsets
Transferrin
Up-Regulation