•TNF-α is a key mediator of graft versus host disease after allogeneic hematopoietic cell transplantation.•Anti-TNF-α drugs are used to treat steroid-refractory graft versus host disease, but they ...are not effective in some patients.•TNFR2 signaling promotes the function of regulatory CD4+FoxP3+ T cells, which suppress adverse graft versus host reactions.•TNFR2 signaling affects the balance between graft versus tumor and graft versus host disease.•Targeting the TNF-α/TNFR2 pathway could be an option for the prevention and the treatment of graft versus host disease.
Tumor necrosis factor-α (TNF-α) signaling through TNF receptor 2 (TNFR2) plays a complex immune regulatory role in allogeneic hematopoietic cell transplantation (HCT). TNF-α is rapidly released in the circulation after the conditioning regimen with chemotherapy and/or radiotherapy. It activates the function of donor alloreactive T cells and donor Natural Killer cells and promotes graft versus tumor effects. However, donor alloreactive T cells also attack host tissues and cause graft versus host disease (GVHD), a life-threatening complication of HCT. Indeed, anti-TNF-α therapy has been used to treat steroid-refractory GVHD. Recent studies have highlighted another role for TNFR2 signaling, as it enhances the function of immune cells with suppressive properties, in particular CD4+Foxp3+ regulatory T cells (Tregs). Various clinical trials are employing Treg-based treatments to prevent or treat GVHD. The present review will discuss the effects of TNFR2 signaling in the setting of allogeneic HCT, the implications for the use of anti-TNF-α therapy to treat GVHD and the clinical perspectives of strategies that specifically target this pathway.
Natural killer (NK) cells are primed to kill by several activating receptors. NK cell killing of autologous cells is prevented because NK cells coexpress inhibitory receptors (killer cell ...immunoglobulin-like receptors KIR) that recognize groups of (self) major histocompatibility complex class I alleles. Because KIRs are clonally distributed, the NK cell population in any individual are constituted of a repertoire with a variety of class I specificities. NK cells in the repertoire mediate alloreactions when the allogeneic targets do not express the class I alleles that block them. After haploidentical hematopoietic transplantation, NK cell-mediated donor-versus-recipient alloresponses reduce the risk of relapse in acute myeloid leukemia patients while improving engraftment and protecting against graft-versus-host disease. High-resolution molecular HLA typing of recipient and donor, positive identification of donor KIR genes, and, in some cases, functional assessment of donor NK clones identify haploidentical donors who are able to mount donor-versus-recipient NK alloreactions.
PURPOSE OF REVIEWThis review focuses on advances in the field of natural killer (NK) cell alloreactivity as a form of immunotherapy in the setting of allogeneic haematopoietic transplantation.
RECENT ...FINDINGSRecent research has focused on mechanisms underlying the acquisition of function by NK cells after haematopoietic transplantation, on the therapeutic impact of NK-cell alloreactivity in various forms of transplantation and in adoptive immunotherapy. Finally, studies have highlighted the role of NK-cell responses in viral infections after transplantation.
SUMMARYDonor-versus-recipient NK-cell alloreactivity is established as a key therapeutic element in human leukocyte antigen haplotype-mismatched haematopoietic transplants in adult acute myeloid leukaemia (AML) and paediatric acute lymphoblastic leukaemia (ALL). NK-cell allotherapy for leukaemia is deployed through stem cell transplantation (and ensuing NK-cell reconstitution) across killer-cell immunoglobulin-like receptor ligand mismatches. Donor-derived NK cells were also reported to respond to cytomegalovirus by acquiring features that are reminiscent of the specificity and memory of adaptive (T-cell) immune responses. As NK cells are the earliest immune cells to recover after transplant, this observation suggests they may contribute to controlling viral reactivation early after transplant.
Although the optimal donor for allogeneic hematopoietic stem cell transplantation is a human leukocyte antigen (HLA)-matched sibling, 75% of patients do not have a match and alternatives are matched ...unrelated volunteers, unrelated umbilical cord blood units, and full HLA-haplotype-mismatched family members. This review will focus on the open issues of allogeneic hematopoietic transplantation and on the benefits of natural killer (NK) cell alloreactivity and its underlying mechanisms. Donor-versus-recipient NK cell alloreactivity derives from a mismatch between inhibitory receptors for self major histocompatibility complex (MHC) class I molecules on donor NK clones and the MHC class I ligands on recipient cells. These NK clones sense the missing expression of the self MHC class I allele on the allogeneic targets (“missing self”) and mediate alloreactions. Here, we review the translation of NK cell allorecognition into the clinical practice of allogeneic hematopoietic transplantation and discuss how it has opened innovative perspectives in the cure of leukemia.
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 × 106/kg), Tregs (mean 2.5 × 106/kg), and Tcons (mean 1.1 × 106/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.
•Haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents high-risk acute leukemia relapse.•The GVL effect is separated from GVHD even across major HLA barriers.
Inhibitory killer cell immunoglobulin receptors (KIR) bind to major histocompatibility complex antigens. Concise knowledge of KIR ligands allows prediction of natural killer (NK)–cell alloreactivity ...after hematopoietic stem cell transplantation. KIR3DL1 binds to the Bw4 epitope on HLA-B antigens. Although the same epitope is also found on 4 HLA-A antigens (HLA-A23/24/25/32), these are not currently regarded as KIR3DL1 ligands. We show that expression of HLA A*2301, A*2402, or A*3201 but not HLA A*2501 protects target cells from lysis by KIR3DL1+ NK cells. KIR3DL1+ NK cells from donors expressing the Bw4 epitope on an HLA-A antigen only are fully functional and capable of lysing Bw4− target cells. HLA A25 differs at amino acid 90, close to the serologic Bw4 epitope, from A23/24/32 and from Bw4+ HLA-B antigens. These data suggest that HLA-A antigens should be taken into consideration when assessing the potential for NK alloreactivity after hematopoietic stem cell transplantation.
In acute myeloid leukemia (AML), alloreactive natural killer (NK) cells are crucial mediators of immune responses after haploidentical stem cell transplantation. Allogeneic NK cell infusions have ...been adoptively transferred with promising clinical results. We aimed at determining whether the composition of NK graft in terms of frequency of alloreactive NK cells influence the clinical response in a group of elderly AML patients undergoing NK immunotherapy.
Seventeen AML patients, in first complete remission (CR; median age 64 years, range 53-73) received NK cells from haploidentical KIR-ligand-mismatched donors after fludarabine/cyclophosphamide chemotherapy, followed by IL2. To correlate donor NK cell activity with clinical response, donor NK cells were assessed before and after infusion.
Toxicity was moderate, although 1 patient died due to bacterial pneumonia and was censored for clinical follow-up. With a median follow-up of 22.5 months (range, 6-68 months), 9 of 16 evaluable patients (0.56) are alive disease-free, whereas 7 of 16 (0.44) relapsed with a median time to relapse of 9 months (range, 3-51 months). All patients treated with molecular disease achieved molecular CR. A significantly higher number of donor alloreactive NK cell clones was observed in responders over nonresponders. The infusion of higher number of alloreactive NK cells was associated with prolonged disease-free survival (0.81 vs. 0.14, respectively;P= 0.03).
Infusion of purified NK cells is feasible in elderly AML patients as post-CR consolidation strategy. The clinical efficacy of adoptively transferred haploidentical NK cells may be improved by infusing high numbers of alloreactive NK cells.
Because activating killer cell immunoglobulinlike receptors (KIRs) are heterogeneously expressed in the population, we investigated the role of donor activating KIRs in haploidentical hematopoietic ...transplants for acute leukemia. Transplants were grouped according to presence vs absence of KIR-ligand mismatches in the graft-vs-host direction (ie, of donor-vs-recipient natural killer NK-cell alloreactivity). In the absence of donor-vs-recipient NK-cell alloreactivity, donor activating KIRs had no effects on outcomes. In the 69 transplant pairs with donor-vs-recipient NK-cell alloreactivity, transplantation from donors with KIR2DS1 and/or KIR3DS1 was associated with reduced risk of nonrelapse mortality, largely infection related (KIR2DS1 present vs absent: hazard ratio HR, 0.25; P = .01; KIR3DS1 present vs absent: HR, 0.18; P = .006), and better event-free survival (KIR2DS1 present vs absent: HR, 0.31; P = .011; KIR3DS1 present vs absent: HR, 0.30; P = .008). Transplantation from donors with KIR2DS1 and/or KIR3DS1 was also associated with a 50% reduction in infection rate (P = .003). In vitro analyses showed that KIR2DS1 binding to its HLA-C2 ligand upregulated inflammatory cytokine production by alloreactive NK cells in response to infectious challenges. Because ∼40% of donors able to exert donor-vs-recipient NK-cell alloreactivity carry KIR2DS1 and/or KIR3DS1, searching for them may become a feasible, additional criterion in donor selection.
•Haploidentical transplantation from KIR ligand–mismatched donors with activating KIRs reduces nonrelapse mortality and improves survival.•Activating KIR genetics should be considered when selecting donors for T cell–depleted haploidentical hematopoietic transplantation.
The authors of this study found that single-nucleotide polymorphisms in long pentraxin 3 (PTX3) were associated with the development of invasive aspergillosis after hematopoietic stem-cell ...transplantation.
Long pentraxin 3 (PTX3) is a soluble pattern-recognition receptor produced by phagocytes and nonimmune cells at sites of inflammation or injury. In addition to its major role in female fertility and vascular biology,
1
PTX3 has a nonredundant role in modulating various effector pathways involved in immune resistance to
Aspergillus fumigatus,
including activating innate immune cells
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and driving protective adaptive immunity.
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PTX3 forms complexes on the conidial surface of the fungus and acts as an opsonin, enhancing recognition and phagocytosis of conidia through mechanisms that depend on Fcγ receptor, CD11b, and complement.
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The interaction of PTX3 with the yeast phase of . . .
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