ایمونولوژیک پیوند سلول بنیادی آلوژنیک در مقابل میزبان و لوسمی

ABSTRACT Immunologic Outcomes of Allogeneic Stem Cell Transplantation: Graft-Versus-Host and Graft-Versus-Leukemia Responses and Implications for Future Therapy

1.1 Hematopoietic Stem Cell Transplantation

The recognition that relatively small numbers of hematopoietic stem cells (HSCs) can regenerate the bone marrow function facilitated the use of high doses of chemotherapy and/or radiation [1] for the treatment of human malignancies and other diseases such as bone marrow failure syndromes, primary immune deficiencies, enzymopathies, and hemoglobinopathies [2]. Initially the procedure consisted of high-dose therapy (HDT, chemotherapy or radiation) followed by bone marrow transplantation (BMT). Later it was realized that HSCs are contained in umbilical cord blood and can also be mobilized and collected from the peripheral blood with apheresis. The donor of stem cells can be the patient (autologous hematopoietic stem cell transplantation, auto-HCT) or someone else (allogeneic hematopoietic stem cell transplantation, allo-HCT). This can be either an HLA-matched sibling donor (MSD allo-HCT), a haploidentical relative (haplo-HCT), or someone unrelated but HLA-matched with the patient (matched unrelated donor or MUD allo- HCT). In umbilical cord blood stem cell transplantation (UCB-HCT) the donor is usually unrelated.

1.2 Graft-Versus-Host Disease and Graft-Versus-Tumor Effect

Early in the HCT era, it was apparent that a subset of patients developed a declining course with evidence of inflammation in various organ systems, which in some cases could be lethal. These patients frequently did not have relapse of their malignancy or obvious infection and a term “secondary disease” and later “graft-versushost disease” (GVHD) (reviewed in [3–5]) was coined to define this process. It became apparent from animal models and in the human clinical setting that GVHD was mediated mainly by alloreactive T cells, since the incidence of GVHD was low in the setting of syngeneic (i.e., identical twin), autologous or T cell-depleted HCT (TCD allo-HCT).

However, it was also recognized that the relapse rates of malignancies were lower after allo-HCT than after auto-HCT. Moreover, relapses were higher after TCD allo-HCT but lower in patients with GVHD (especially chronic GVHD), implying that not only the HDT but also the donor immune system was critical to keep recipients in remission. Subsequently, it was shown that for patients relapsing without GVHD following allo-HCT, the infusion of donor lymphocytes (DLI) could make the malignancy regress or enter another remission, in some cases without the development of GVHD following DLI. The terms graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) have been used to describe this donor immune reactivity against the recipient malignancy [6]. Since the recognition of GVL in allo-HCT, many transplanters have decreased the intensity of HDT, especially for slowgrowing malignancies (e.g., follicular lymphomas). We call these attenuated therapies reduced-intensity conditioning (RIC) [7]. An extreme extension of this approach is to rely almost exclusively on GVL and to give only modest doses of immunosuppressive therapy (to avoid graft rejection, mediated by residual host immunity) and then to allow the donor immune system fight the neoplasm (nonmyeloablative conditioning, NMA). The introduction of RIC and NMA conditioning regimens allowed the application of HCT to older patients or those with comorbid conditions, which is critical given that most diseases curable by HCT increase in incidence with age. Given the significant morbidity and mortality associated with GVHD and the curative potential of GVT, a critical problem faced by transplant immunologists has been the dissociation of these two phenomena.

1.3 Acute GVHD

Understanding the pathogenesis of GVHD (and of GVL) is essential to facilitate the selective manipulation of these clinical events after HCT. However, a critical problem is that GVHD is an extremely pleomorphic entity. There is an acute and a chronic form (aGVHD and cGVHD, respectively) and also an overlap syndrome that can combine features of both. Initially defined by the time of their onset (day +100 after HCT being the date that separated the two forms), aGVHD and cGVHD are now more appropriately distinguished by their clinical manifestations. aGVHD usually affects the skin, the gastrointestinal (GI) tract and the liver, whereas cGVHD typically involves mucosal surfaces, the eyes and the skin (but can involve nearly any organ system). More severe manifestations of aGVHD may include GI disease (e.g., diarrhea, nausea, emesis, abdominal pain, or failure to thrive, depending on the segment of the GI tract that is targeted), and signs of severe hepatic dysfunction (jaundice, encephalopathy, bleeding, hypoalbuminemia) and severe skin involvement (e.g., generalized maculopapular rash that can progress to erythroderma and exfoliation) [8]. If aGVHD happens before day +14 (usually before engraftment), this is called hyper-acute GVHD and is associated with an adverse prognosis [9]. We now also recognize that a late-onset form of aGVHD may occur even well beyond post-transplant day +100 (delayed-onset aGVHD), in some cases due to the tapering of immunosuppression.

1.4 Chronic GVHD

Chronic GVHD also manifests quite variably [10]. Patients may have sicca symptoms (xeropthalmia, xerostomia) with or without arthralgias/arthritis, oral lichenoid changes, skin rash, poikiloderma, skin lichenification, and/or systemic sclerosis (scleroderma), eosinophilic fasciitis or polymyositis. They can also develop liver dysfunction and cholestasis, anorexia, nausea, emesis, weight loss, malnutrition, bronchiolitis obliterans (BO), or cryptogenic organizing pneumonia (COP, formerly BOOP). Other less common manifestations include glomerulonephritis with or without nephrotic syndrome, hypogonadism, and other hormonal deficiencies. Serosal inflammation with pleural effusions or ascites and nervous system involvement are very rare.