Regenerative failure at barrier surfaces and maladaptive repair leading to fibrosis are hallmarks of graft-versus-host disease (GVHD). Although immunosuppressive treatment can control inflammation, ...impaired tissue homeostasis leads to prolonged organ damage and impaired quality of life. In this Blood Spotlight, we review recent research that addresses the critical failures in tissue regeneration and repair that underpin treatment-resistant GVHD. We highlight current interventions designed to overcome these defects and provide our assessment of the future therapeutic landscape.
The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of ...the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3-dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs.
After allogeneic blood or bone marrow transplantation, donor T cells interact with a distorted antigen-presenting cell (APC) environment in which some, but not all, host APCs are replaced by APCs ...from the donor. Significantly, host APCs are required for the priming of acute graft-versus-host disease (GVHD). Donor APCs play a lesser role in the induction of acute GVHD despite their predicted capacity to cross-present host antigens. In contrast, donor APCs may play a role in perpetuating the tissue injury observed in chronic GVHD. Host APCs are also required for maximal graft-versus-leukemia responses. Recent studies have suggested potential strategies by which the continued presence of host APCs can be exploited to prime strong donor immunity to tumors without the induction of GVHD.
The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease ...(NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells
. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift toward a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.
Allogeneic transplantation for lymphoma Chakraverty, Ronjon; Mackinnon, Stephen
Journal of clinical oncology,
2011-May-10, Letnik:
29, Številka:
14
Journal Article
Recenzirano
Historically, high levels of treatment-related mortality restricted the use of standard myeloablative allogeneic stem-cell transplantation to a minority of young and fit patients with lymphoma. Over ...the last decade, increasing numbers of patients with lymphoma have undergone allogeneic stem-cell transplantation using reduced-intensity protocols that are associated with lower toxicity and reduced transplantation-related mortality. Graft-versus-lymphoma effects contribute to the therapeutic effect in patients with indolent or Hodgkin's lymphoma. However, definitive evidence for efficacy of this strategy is lacking because most patients undergoing transplantation do so after failure of several lines of treatment, leaving no obvious comparator arm for randomized controlled studies. Nevertheless, encouraging results have been reported for selected patients for most lymphoma subtypes, with pretransplantation disease status emerging as the most important predictor of outcome. The major long-term toxicity is chronic graft-versus-host disease that contributes to ill health in a significant minority of survivors. In the future, risk-adapted trials that evaluate reduced-intensity allogeneic transplantation in patients with predicted poor outcomes with immunochemotherapy or autologous transplantation will be important in determining the role of this treatment.
The skin is the most common target organ affected by graft-versus-host disease (GVHD), with severity and response to therapy representing important predictors of patient survival. Although many of ...the initiating events in GVHD pathogenesis have been defined, less is known about why treatment resistance occurs or why there is often a permanent failure to restore tissue homeostasis. Emerging data suggest that the unique immune microenvironment in the skin is responsible for defining location- and context-specific mechanisms of injury that are distinct from those involved in other target organs. In this review, we address recent advances in our understanding of GVHD biology in the skin and outline the new research themes that will ultimately enable design of precision therapies.
Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct ...poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematological improvement and became permanently transfusion and growth factor-independent. In multivariate analysis, parameters significantly associated with recovery were shared CMV seronegative status for recipient/donor, the absence of active infection and matched recipient/donor sex. Recovery was similar in patients with mixed and full donor chimerism. Five -year overall survival was 74.4% (95% CI 59-89) in patients demonstrating complete recovery, 16.7% (95% CI 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in patients with no response. In patients with count recovery, those with poor graft function in 1-2 lineages had superior 5-year overall survival (93.8%, 95% CI 82-99) than those with tri-lineage failure (53%, 95% CI 34-88). New strategies including cytokine or agonist support, or second transplant need to be investigated in patients who do not recover.
Stem cell transplantation is used widely in the management of a range of diseases of the hemopoietic system. Patients are immunosuppressed profoundly in the early posttransplant period, and ...reactivation of cytomegalovirus (CMV) remains a significant cause of morbidity and mortality. Adoptive transfer of donor-derived CMV-specific CD8+ T cell clones has been shown to reduce the rate of viral reactivation; however, the complexity of this approach severely limits its clinical application. We have purified CMV-specific CD8+ T cells from the blood of stem cell transplant donors using staining with HLA-peptide tetramers followed by selection with magnetic beads. CMV-specific CD8+ cells were infused directly into nine patients within 4 h of selection. Median cell dosage was 8.6 x 10(3)/kg with a purity of 98% of all T cells. CMV-specific CD8+ T cells became detectable in all patients within 10 d of infusion, and TCR clonotype analysis showed persistence of infused cells in two patients studied. CMV viremia was reduced in every case and eight patients cleared the infection, including one patient who had a prolonged history of CMV infection that was refractory to antiviral therapy. This novel approach to adoptive transfer has considerable potential for antigen-specific T cell therapy.
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