Lethal graft-vs-host disease across major histocompatibility barriers: requirement for leucyl-leucine methyl ester sensitive cytotoxic T cells.

Abstract

L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) is selectively toxic for human natural killer (NK) cells and cytotoxic T lymphocytes (CTL) at both the precursor and effector stage of differentiation. The present studies explored the effects of Leu-Leu-OMe on murine spleen cell function. Leu-Leu-OMe exposure removed NK function from murine spleen cells but spared their capacity to proliferate in response to lipopolysaccharide and Con A. The capacity to generate CTL from both L3T4 (+) and Lyt-2 (+) precursors was lost after Leu-Leu-OMe treatment, whereas alloantigen-induced proliferation and interleukin 2 (IL 2) production by L3T4 (+) T helper cells remained intact. Lethal graft vs host disease (GVHD), which developed in irradiated (C57BL/6 X DBA/2)F1 recipients of C57BL/6 bone marrow and spleen cells was completely prevented by Leu-Leu-OMe treatment of donor cells. In contrast depletion of Lyt-2 positive cells from the donor inoculum did not prevent acute GVHD in this fully major histo-compatibility complex (MHC) incompatible strain combination. However, Leu-Leu-OMe treatment of the Lyt-2 depleted inoculum completely prevented lethal GVHD, although the treated cells retained the capacity to proliferate and secrete IL 2 normally after in vitro stimulation with (C57BL/6 X DFA/2)F1 spleen cells. These findings indicate that L3T4 (+) T helper cells alone are unable to initiate lethal GVHD in this H-2 incompatible strain combination. Rather, lethal GVHD requires the transfer of a Leu-Leu-OMe sensitive T cell subset, likely to be thymus educated pre-CTL. Leu-Leu-OMe treatment should provide a useful way to delineate subpopulations of cells involved in the production of lethal GVHD and an approach to preventing this complication of bone marrow transplantation.

• Authors: D L Thiele, M R Charley, J A Calomeni, P E Lipsky
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 138 Issue 1 Pg. 51-7 (Jan 01 1987) ISSN: 0022-1767 [Print] United States
• PMID: 2946780 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Differentiation, T-Lymphocyte
• Antigens, Ly
• Antigens, Surface
• Dipeptides
• H-2 Antigens
• Interleukin-2
• leucyl-leucine-methyl ester

Topics

• Animals
• Antigens, Differentiation, T-Lymphocyte
• Antigens, Ly (analysis)
• Antigens, Surface (analysis)
• Bone Marrow Transplantation
• Cytotoxicity, Immunologic (drug effects)
• Dipeptides (pharmacology)
• Graft vs Host Disease (immunology)
• H-2 Antigens (analysis)
• Interleukin-2 (biosynthesis)
• Killer Cells, Natural (immunology)
• Lymphocyte Activation (drug effects)
• Major Histocompatibility Complex
• Mice
• T-Lymphocytes (classification, immunology)
• T-Lymphocytes, Cytotoxic (drug effects, immunology)
• T-Lymphocytes, Helper-Inducer (immunology)