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CHAPTER 9 Graft‐versus‐host disease and late effects after hematopoietic stem cell transplantation
David Michonneau, Aurélien Sutra del Galy, and Gérard Socié
Hematology Transplantation, APHP Hospital Saint Louis and Université de Paris, Paris, France
Université de Paris & INSERM U976, Paris, France
Introduction
Large numbers of patients now survive long‐term following hematopoietic stem cell transplantation (HSCT), and late clinical effects of HSCT are, thus, of major concern. Chronic graft‐versus‐host disease (cGVHD), and the associated immunodeficiency are the primary causes of transplant‐related mortality late after allogeneic HSCT and contribute directly or indirectly to most late complications. Despite the advent of new treatment modalities the incidence of cGVHD has remained high, related to several changes in clinical HSCT practice: (i) the expanded use of HLA matched unrelated and HLA non‐identical related donors; (ii) the increasing use of HSCT in older patients; (iii) the increasing use of viable donor lymphocyte infusions after HSCT to treat relapsed disease or to achieve full donor chimerism after non‐myeloablative transplantation; (iv) the increasing use of peripheral blood stem cells instead of bone marrow as a source of stem cells. In addition to cGVHD and its therapy, the major risk factor for late complications after HSCT is the use of irradiation in the pretransplant conditioning regimen.
cGVHD — which was originally defined as occurring after the first 100 days post‐HSCT — is now known to have a characteristic clinical presentation, which resembles autoimmune vascular diseases and is distinct from that of acute GvHD [1–5]. cGVHD occurs in 30–65% of allogeneic HSCT recipients, can be highly debilitating in its extensive form and has a 5‐year mortality rate of 30–50% that is mainly due to immune dysregulation and opportunistic infections. The pathophysiology of cGVHD mainly depends on the polarization of CD4+ T cells into T‐helper 2 (TH2) cells, but there are six hallmarks that are unique to this syndrome (reviewed in Zeiser and Blazer [5]; Blazer et al. [6]. The first feature is damage to the thymus (a), which can be caused by the conditioning regimen or, more importantly, by prior occurrence of acute GvHD. This damage results in decreased negative selection of alloreactive CD4+ T cells (b). There is immune deviation to a TH2‐type cytokine response (c), which includes the production of interleukin‐4 (IL‐4), IL‐5 and IL‐11. This response leads to the release of fibrogenic cytokines — such as IL‐2, IL‐10 and transforming growth factor‐β1 (TGFβ1) — and the activation of macrophages that produce platelet‐derived growth factor (PDGF) and TGFβ1 (d). These molecules induce the proliferation and activation of tissue fibroblasts. Low numbers of regulatory T (Treg) cells are the fifth hallmark (e), and finally there is B cell dysregulation (f), which leads to the emergence of autoreactive B cells and the production of autoreactive antibodies. It has been suggested that autoreactive B cell activation may be due to the presence of high levels of B cell‐activating factor (BAFF) in the lymphoid microenvironment. All these events contribute to an autoimmune‐like systemic syndrome that is associated with fibroproliferative changes. These changes can occur in almost any organ of the body but mainly affect oral and ocular mucosal surfaces and the skin, lungs, kidneys, liver and gut.
Immune reconstitution occurs gradually over time (generally 12–24 months) and is slower for allogeneic recipients, particularly those receiving umbilical cord blood, HLA‐mismatched or T‐cell depleted grafts and in survivors