Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease

被引:30
作者
Liu, JL
Anderson, BE
Robert, ME
McNiff, JM
Emerson, SG
Shlomchik, WD
Shlomchik, MJ
机构
[1] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA
[3] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA
[4] Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA
[5] Univ Penn, Sch Med, Dept Med, Sect Hematol & Oncol, Philadelphia, PA 19104 USA
关键词
D O I
10.1182/blood.V98.12.3367
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality of allogeneic stem cell transplantation. Strategies to control GVHD while maintaining graft versus leukemia (GVL) include herpes simplex virus thymidine kinase (HSV-tk) gene transduction of donor T cells followed by treatment with ganciclovir (GCV). Alternatively, GVHD and GVL may be mediated by distinct processes. In this regard, whether cytokine polarization occurs and to what degrees various subsets of cytokine-producing T cells mediate GVHD or GVL has been an active area of research using cytokine or cytokine antibody infusion or genetically deficient mice. This study takes a different approach that allows simultaneous investigation into both the mechanisms underlying GVHD reactions and the efficacy of HSV-tk suicide gene-based T-cell deletion. A source of donor T-cells, splenocytes from mice transgenic for HSV-tk controlled by elements of either the interleukin-2 (IL-2) or IL-4 promoters (IL-2-tk and IL-4-tk, respectively) Was used, thus allowing investigation into the roles of T1 and T2 cells in ongoing GVHD reactions. To assess treatment rather than prevention of GVHD, GCV was started at peak disease. Remarkably, treatment at this late time point rescued mice from the clinical effects of GVHD caused by T cells expressing either transgene. Thus, both T1 and T2 calls play an important role in clinical GVHD in a minor histocompatibility antigen-mismatched setting. In addition, because clinical disease was reversible even at its maximum, these observations provide controlled evidence that this strategy of treating ongoing GVHD could be effective clinically. (Blood. 2001;98:3367-3375) (C) 2001 by The American Society of Hematology.
引用
收藏
页码:3367 / 3375
页数:9
相关论文
共 79 条
[1]   DIFFERENTIAL CYTOKINE EXPRESSION IN ACUTE AND CHRONIC MURINE GRAFT-VERSUS-HOST-DISEASE [J].
ALLEN, RD ;
STALEY, TA ;
SIDMAN, CL .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1993, 23 (02) :333-337
[2]   Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation [J].
Asai, O ;
Longo, DL ;
Tian, ZG ;
Hornung, RL ;
Taub, DD ;
Ruscetti, FW ;
Murphy, WJ .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (09) :1835-1842
[3]  
BAKER KS, 1995, BONE MARROW TRANSPL, V15, P595
[4]   The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice [J].
Baker, MB ;
Altman, NH ;
Podack, ER ;
Levy, RB .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 183 (06) :2645-2656
[5]   T cell-depleted bone marrow transplantation and delayed T cell add-back to control acute GVHD and conserve a graft-versus-leukemia effect [J].
Barrett, AJ ;
Mavroudis, D ;
Tisdale, J ;
Molldrem, J ;
Clave, E ;
Dunbar, C ;
Cottler-Fox, M ;
Phang, S ;
Carter, C ;
Okunnieff, P ;
Young, NS ;
Read, EJ .
BONE MARROW TRANSPLANTATION, 1998, 21 (06) :543-551
[6]  
Blazar BR, 1996, J IMMUNOL, V157, P3250
[7]   INTERLEUKIN-10 ADMINISTRATION DECREASES SURVIVAL IN MURINE RECIPIENTS OF MAJOR HISTOCOMPATIBILITY COMPLEX DISPARATE DONOR BONE-MARROW GRAFTS [J].
BLAZAR, BR ;
TAYLOR, PA ;
SMITH, S ;
VALLERA, DA .
BLOOD, 1995, 85 (03) :842-851
[8]  
Blazar BR, 1997, J IMMUNOL, V158, P29
[9]   HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia [J].
Bonini, C ;
Ferrari, G ;
Verzeletti, S ;
Servida, P ;
Zappone, E ;
Ruggieri, L ;
Ponzoni, M ;
Rossini, S ;
Mavilio, F ;
Traversari, C ;
Bordignon, C .
SCIENCE, 1997, 276 (5319) :1719-1724
[10]   Potential and limitations of HSV-TK-transduced donor peripheral blood lymphocytes after allo-BMT [J].
Bonini, C ;
Bordignon, C .
HEMATOLOGY AND CELL THERAPY, 1997, 39 (05) :273-274