Summary
This review examines the evidence that bone marrow failure (BMF) in aplastic anaemia (AA) is due to loss of haematopoietic stem cells (HSCs), which, in turn, is caused by deranged immunity ...and inflammation. We also consider how the course of the disease and the response to immuno‐suppressive therapy are influenced by the nature and specificity of the pathogenic process. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl‐phosphatidyl‐inositol ‐specific auto‐immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. A similar process, although less effective, may operate when the auto‐immune attack is against a human leucocyte antigen (HLA) molecule and an HLA mutation has produced a clone missing that molecule. We then discuss the significance of other mutant clones that are frequently found in AA, presumably due to a combination of genetic drift and selection. These clones are not causative of AA, but they emerge in AA and they may be pre‐leukaemic: unlike a PIGA mutant clone, in general they are unable to effectively reconstitute haematopoiesis.
Complement as a target in COVID-19? Risitano, Antonio M; Mastellos, Dimitrios C; Huber-Lang, Markus ...
Nature reviews. Immunology,
06/2020, Letnik:
20, Številka:
6
Journal Article
Therapeutic complement inhibition by eculizumab has revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH) with a major impact on its natural history. Nevertheless, emerging unmet ...clinical needs may benefit from the development of novel complement inhibitors. Novel strategies of complement inhibition exploit different agents targeting C5, as well as compound intercepting the complement cascade at the level of its key component C3, or even upstream at the level of components involved in complement alternative pathway initiation. Many of these agents are already in their clinical development; preliminary data together with a deep understanding of PNH biology may help to anticipate their possible clinical effect. Novel anti‐C5 agents include monoclonal antibodies (even long‐lasting) as well as other small molecules bioavailable by subcutaneous administration; an anti‐C5 small interfering RNA has been developed too. All these anti‐C5 agents seem to recapitulate safety and efficacy of current eculizumab treatment; their main improvement pertains to better patient's convenience due to longer dosing interval and/or possible subcutaneous self‐administration. The possibility of achieving a deeper C5 inhibition has been shown as well, but its actual clinical meaning remains to be elucidated. Upstream complement inhibitors include the anti‐C3 small peptide compstatin (and its derivatives), and small inhibitors of complement factor D or complement factor B. This class of compounds anticipates a possible efficacy in prevention of C3‐mediated extravascular hemolysis, in addition to inhibition of intravascular hemolysis, eventually leading to improved hematological responses. The availability of all these compounds will result soon in a substantial improvement of PNH management.
Acute respiratory distress syndrome (ARDS) is a devastating clinical manifestation of COVID-19 pneumonia and is mainly based on an immune-driven pathology. Mounting evidence suggests that COVID-19 is ...fueled by a maladaptive host inflammatory response that involves excessive activation of innate immune pathways. While a “cytokine storm” involving IL-6 and other cytokines has been documented, complement C3 activation has been implicated as an initial effector mechanism that exacerbates lung injury in preclinical models of SARS-CoV infection. C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101.
Abstract The recent availability of eculizumab as the first complement inhibitor renewed the interest for complement-mediated damage in several human diseases. Paroxysmal nocturnal hemoglobinuria ...(PNH) may be considered the paradigm a disease caused by complement dysregulation specifically on erythrocytes; in fact, PNH is a clonal, non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells which are deficient in some surface proteins, including the two complement regulators CD55 and CD59. As a result, PNH erythrocytes are incapable to modulate on their surface physiologic complement activation, which eventually enables the terminal lytic complement leading to complement-mediated intravascular anemia – the typical clinical hallmark of PNH. In the last decade the anti-C5 monoclonal antibody has been proven effective for the treatment of PNH, resulting in a sustained control of complement-mediated intravascular hemolysis, with a remarkable clinical benefit. Since then, different diseases with a proved or suspected complement-mediated pathophysiology have been considered as candidate for a clinical complement inhibition. At the same time, the growing information on biological changes during eculizumab treatment in PNH have improved our understanding of different steps of the complement system in human diseases, as well as their modulation by current anti-complement treatment. As a result, investigators are currently working on novel strategy of complement inhibition, looking at the second generation of anti-complement agents which hopefully will be able to modulate distinct steps of the complement cascade. Here we review PNH as a disease model, focusing on the observation that led to the development of novel complement modulators; the discussion will be extended to other hemolytic disorders potentially candidate for clinical complement inhibition.
Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman ...T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling.
We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease.
After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval CI, 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% 95% CI, 47.8 to 69.2 and 64.6% 95% CI, 50.9 to 75.3, respectively; P=0.21), as was the rate of overall survival (74.1% 95% CI, 62.7 to 82.5 and 77.9% 95% CI, 66.1 to 86.1, respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005).
The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).