Natural CD4 CD25 FOXP3 regulatory T cells in graftversus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 242

ch 12

Natural CD4 + CD25 + FOXP3 +
regulatory T cells in graft-
versus-host disease

Matthias Edinger, Petra Hoffmann
Department of Hematology and Oncology, University Hospital Regensburg, Germany

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Introduction

Allogeneic hematopoietic stem cell transplantation (SCT) is the treat-
ment of choice for some hereditary and acquired nonmalignant dis-
eases of the hematopoietic system and most frequently applied for the
treatment of resistant or high-risk hematologic malignancies. It was ini-
tially designed as an organ replacement strategy in which the diseased
hematopoiesis is eradicated by the use of high-dose irradiation and/or
myeloablative chemotherapy and then replaced with the hematopoi-
esis of a healthy donor. Yet, it rapidly became evident that the efficacy
of allogeneic SCT does not rely solely on the engraftment of stem cells
and the successful reconstitution of myelopoiesis; in fact it is a cellu-
lar immunotherapy. The main drivers of this immunotherapeutic effect
are cotransplanted donor T cells that either directly recognize HLA after
HLA-mismatched transplantation or respond to minor antigens after
HLA-matched SCT. After their activation, expansion, and differentiation,
allogeneic T cells attack host tissues. The most sensitive targets for such
alloresponses are hematopoietic cells and thus donor T cells contrib-
ute to the eradication of recipient hematopoiesis and thereby mediate
potent graft-versus-leukemia/lymphoma (GVL) effects in patients with
hematologic malignancies. The recognition of these potent donor T-cell
effects led to the introduction of dose-reduced and even nonmyeloabla-
tive conditioning regimens, which are now frequently applied and which
largely rely on these therapeutic donor T cell functions. However, donor T
cells not only recognize hematopoietic antigens, but can also respond to
solid organs and thereby induce acute and/or chronic graft-versus-host
disease (GVHD). Severe GVHD is the main cause for the high morbidity
and mortality after allogeneic SCT and still, to date, we do not possess
reliable predictive tests or markers to identify donor-recipient pairs at
high risk for GVHD development. Thus, prevention of GVHD without
abrogating the beneficial donor T cell effects remains the main chal-
lenge in allogeneic SCT.