T-cell costimulation in graftversus- host disease and graft-versus-leukemia effect - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 192

ch 10

T-cell costimulation in graft-
versus-host disease and
graft-versus-leukemia effect

Xue-Zhong Yu
Department of Immunology and Department of Blood & Marrow Transplantation, H. Lee Moffitt Cancer Center
& Research Institute, and Department of Pathology & Cell Biology and Department of Oncologic Sciences, University of
South Florida, Tampa, Florida, USA
Claudio Anasetti
Department of Blood & Marrow Transplantation and Department of Immunology, H. Lee Moffitt Cancer Center
& Research Institute, and Department of Oncologic Sciences, University of South Florida, Tampa, Florida, USA

195

Introduction

Allogeneic hematopoietic cell transplantation (HCT) is an effective
therapeutic option with a curative potential for many malignant dis-
eases. The therapeutic potential of allogeneic HCT relies on the graft-
versus-tumor (GVT) effect to eradicate residual tumor cells by immu-
nologic mechanisms. Under this therapeutic procedure, graft-versus-
host disease (GVHD) remains the major complication, as it leads to high
morbidity and mortality of the patient. GVHD is initiated by mature
donor T cells that recognize disparate histocompatibility antigens of the
recipient and cause injuries in normal tissues. The pathophysiology of
GVHD development consists several steps [1] : i) priming of the immune
response through conditioning with irradiation or chemotherapy;
ii) T-cell activation and costimulation through alloantigen recognition
and ligation of costimulatory molecules; iii) alloreactive T-cell expan-
sion and differentiation; iv) activated T-cell trafficking into GVHD target
tissues, including gut, liver, skin, and lung; and v) destruction of the tar-
get tissues by effector T cells (Teffs).

The center of GVHD development lies in T-cell activation, prolifera-
tion, and differentiation. It is a well-established concept that a produc-
tive T-cell activation requires two signals: a first signal provided by the
interaction of the antigenic peptide/major histocompatibility complex
(MHC) with the T-cell receptor (TCR) and a second signal derived by the
interaction of costimulatory receptors with their cognate ligands. Semi-
nal studies by Schwartz [2] demonstrated that a TCR signal alone with-
out costimulation resulted in antigen-specific unresponsiveness known