IntroductionA viable option for high-risk, acute leukemia patients without matched donors is hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA)-haploidentical 3-locimismatched family members who were readily available for almost all patients. 1,2 Until the 1990s, full-haplotype-mismatched, T cell-replete transplantations were unsuccessful because donoralloreactive T cells triggered a high incidence of severe graft-versushost disease (GVHD) despite posttransplantation immune suppression. 3,4 The breakthrough came with the use of a megadoses of extensively ex vivo T cell-depleted peripheral blood hematopoietic progenitor cells and a highly myeloablative conditioning regimen containing antithymocyte globulin (ATG), which exerts additional T-cell depletion in vivo. This approach ensures a high rate of primary engraftment in the absence of GVHD, 5 with more than 40% long-term event-free survival and excellent quality of life. 1,2 However, extensive ex vivo and in vivo T-cell depletion delays the recovery of immune responses against pathogens, leading to a high incidence of life-threatening infections. 1,2 Strategies to hasten posttransplantation immune reconstitution without triggering GVHD have included infusion of donor T cells after engineering with a suicide gene, 6 photodynamic purging, 7 and the use of an anti-CD25 monoclonal antibody (mAb) 8 to remove alloreactive cells. An alternative strategy might be based on donor CD4 ϩ CD25 ϩ T-regulatory cells (Tregs). In murine models of HSCT across major histocompatibility complex barriers, CD4 ϩ CD25 ϩ Tregs suppressed lethal GVHD 9 and favored posttransplantation immune reconstitution when coinfused with conventional T cells (Tcons). 10 The main obstacle to clinical application of human Tregs is their paucity in the peripheral blood. Although ex vivo-expanded polyclonal 11 or recipient-specific Tregs 12 were proposed to circumvent this potential barrier, we opted for closed, automated immunoselection 13 of naturally occurring Tregs. In the present study, for the first time in humans, we show that the early infusion of freshly isolated donor Tregs followed by Tcons at the time of full-haplotypemismatched HSCT prevented GVHD while favoring Tconmediated posttransplantation immune reconstitution. MethodsStudy design, conditioning regimen, stem cell mobilization, and supportive careIn 2008, the Umbria Regional Hospital Ethics Committee (CEAS Umbria) approved the protocol entitled "Adoptive Immunotherapy with Natural Regulatory T cells (Treg) and Effector T Cells in Allogeneic Hematopoietic Stem Cell Transplantation from 2-3 Loci Mismatched HLA-Haploidentical Family Donors for Patients with High Risk Haematologic Malignancies" (Protocol No 01/08). Written informed consent was obtained for all patients and donors in accordance with the Declaration of Helsinki. Inclusion criteria were: acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) in remission at high risk of relapse; acute leukemia with primary induction failure, in chemoresist...
Posttransplant relapse is still the major cause of treatment failure in high-risk acute leukemia. Attempts to manipulate alloreactive T cells to spare normal cells while killing leukemic cells have been unsuccessful. In HLA-haploidentical transplantation, we reported that donor-derived T regulatory cells (Tregs), coinfused with conventional T cells (Tcons), protected recipients against graft-versus-host disease (GVHD). The present phase 2 study investigated whether Treg-Tcon adoptive immunotherapy prevents posttransplant leukemia relapse. Forty-three adults with high-risk acute leukemia (acute myeloid leukemia 33; acute lymphoblastic leukemia 10) were conditioned with a total body irradiation-based regimen. Grafts included CD34(+) cells (mean 9.7 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/kg). No posttransplant immunosuppression was given. Ninety-five percent of patients achieved full-donor type engraftment and 15% developed ≥grade 2 acute GVHD. The probability of disease-free survival was 0.56 at a median follow-up of 46 months. The very low cumulative incidence of relapse (0.05) was significantly better than in historical controls. These results demonstrate the immunosuppressive potential of Tregs can be used to suppress GVHD without loss of the benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided insights into the mechanisms underlying separation of GVL from GVHD, suggesting the GVL effect is due to largely unopposed Tcon alloantigen recognition in bone marrow.
The C-type lectin receptor Dectin-1 plays a pivotal role in antifungal immunity. In this study, the recently characterized human DECTIN1 Y238X early stop codon polymorphism leading to diminished Dectin-1 receptor activity was studied in relation to invasive aspergillosis susceptibility and severity in patients receiving hematopoietic stem cell transplantation. We found that the presence of the DECTIN1 Y238X polymorphism in either donors or recipients of hematopoietic stem cell transplantation increased susceptibility to aspergillosis, with the risk being highest when the polymorphism was present simultaneously in both donors and recipients (adjusted hazard ratio ؍ 3.9; P ؍ .005). Functionally, the Y238X polymorphism impaired the production of interferon-␥ and interleukin-10 (IL-10), in addition to IL-1, IL-6, and IL-17A, by human peripheral mononuclear cells and Dectin-1 on human epithelial cells contributed to fungal recognition. Mechanistically, studies on preclinical models of infection in intact or bone marrow-transplanted Dectin-1 knockout mice revealed that protection from infection requires a distinct, yet complementary, role of both donor and recipient Dectin-1. This study discloses Dectin-1 deficiency as a novel susceptibility factor for aspergillosis in high-risk patients and identifies a previously unsuspected role for Dectin-1 in antifungal immunity that is the ability to control both resistance and tolerance to the fungus contingent on hematopoietic/ nonhematopoietic compartmentalization. (Blood. 2010;116(24):5394-5402) IntroductionAspergillus spp are ubiquitous in nature, and the spectrum of diseases they cause is myriad, including saprophytic colonization of preexisting cavities (aspergilloma), allergic asthma, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis occurring as a complication of bronchial asthma or cystic fibrosis, and disseminated disease associated with high mortality rates in patients with hematologic malignancies and recipients of solid organs and stem cell transplantations. 1 Immunocompetent and nonatopic subjects are relatively resistant to infections, and disease occurs in the setting of host damage. 2 The association of persistent inflammation with intractable infection is common in nonneutropenic patients after hematopoietic stem cell transplantation (HSCT) as well as in allergic fungal diseases. 2 The current understanding of the pathophysiology underlying Aspergillus infection and disease highlights a truly bipolar nature of the inflammatory process in infection. Early inflammation prevents or limits infection, but an uncontrolled response may eventually oppose disease eradication. This condition is crucially exemplified in mice with chronic granulomatous disease, in which an intrinsic, genetically determined failure to control inflammation to sterile fungal components determines the animals' inability to resolve an actual infection with A fumigatus. 3 A main implication of these findings is that, at least in specific clinical settings, it is an exag...
Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8 ؉ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8 ؉ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4 ؉ and CD8 ؉ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHCrestricted, CD8 ؉ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protective CD8 ؉ T cells both in mice and in patients receiving stem-cell transplantations. Therefore, TLR3 essentially promotes antifungal memory CD8 ؉ T-cell responses and its deficiency is a novel susceptibility factor for aspergillosis in high-risk patients. IntroductionTLR3 plays a key role in modulating inflammation and innate immunity in the airway. Although best known for recognition of viral double-stranded RNA (dsRNA) and its synthetic analog polyinosinic:polycytidylic acid [poly(I:C)], 1 TLR3 also recognizes endogenous ligands, 2 including heterologous RNA released from or associated with necrotic cells or generated by in vitro transcription. 3 Therefore, TLR3, together with other intracellular signaling proteins, 4 induces or otherwise modulates innate immune responses and inflammation in settings that are not associated with viral dsRNA. TLR3 signaling may also modulate adaptive immune responses by providing cross-priming of cytotoxic T lymphocytes through signaling in dendritic cells (DCs) 5,6 via type I IFNs 7 and in the absence of CD4 ϩ T-cell help. 8 Therefore, it is not surprising that people with mutations in key TLR3 signaling components have a selective immunodeficiency manifested by recurrent episodes of herpes simplex virus 1 encephalitis 9,10 or enteroviral myocarditis/cardiomyopathy. 11 Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. Humans inhale hundreds of conidia every day without adverse consequences, 12 except for a minority of persons in whom defense systems fail and a life-threatening form of disease can develop. CD4 ϩ and CD8 ϩ T cells are present in the human T-cell repertoire to the fungus 13-15 and adoptive transfer of A fumigatus-specific CD4 ϩ T cells conferred protection against invasive fungal infection. 15,16 Recent studies indicate a role for TLR3 in murine aspergillosis. By functioning as an endogenous sensor of fungal RNA, 17 TLR3 mediates expression of the enzyme indoleamine 2,3-dioxygenase (IDO) on both epithelial cells 18 and DCs,19 contributing to the local regulation of innate and adaptive inflammation to the fungus. However, the findings that protective memory CD8 ϩ T cells are induced against fungi 20-23 suggest a possible rol...
Key Points Low doses of adoptively transferred donor CD4+ iNKT cells protect from GVHD while preserving graft-versus-tumor effects. Donor CD4+ iNKT cells inhibit proliferation of alloreactive T cells and promote robust expansion of donor Tregs.
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