Investigation of the mechanism of drug-induced autoimmune hemolytic anemia in cynomolgus monkeys elicited by a repeated-dose of a humanized monoclonal antibody drug. (65/384)

We investigated the mechanism of hemolytic anemia detected in a repeated-dose toxicity study using cynomolgus monkeys that were treated with a humanized antibody drug. This drug was an IgG1 monoclonal antibody (MoAb) that binds to the human HM1.24 antigen named anti-HM1.24 MoAb. The presence of the HM1.24 antigen on the erythrocyte membranes and the erythrocyte agglutination following the addition of anti-HM1.24 MoAb was examined. In addition, an indirect Coombs' test, a hemolysis assay and the measurement of anti-single stranded-DNA antibodies were performed using test animal serum or plasma. The specific binding of FITC- and 125I-labeled anti-HM1.24 MoAb to the erythrocyte membrane was not observed. HM1.24 antigen was not identified on the erythrocyte membranes. However, a high concentration (more than 713 microg/mL) of anti-HM1.24 MoAb hemagglutinated the erythrocyte suspensions. The cause of this agglutination was unclear, but it is assumed that the non-specific binding and/or adhesion caused the direct agglutination. In the examination using test serum from the anemic monkeys, a positive reaction in the indirect Coombs' test was noted. Moreover, in these Coombs' test-positive animals, the production of anti-single stranded-DNA antibodies was sequentially increased. In the female monkey sacrificed in extremis due to severe anemia, an in vitro hemolytic reaction was detected attributable to complement activation. From these results, the hemolytic anemia detected in the repeated-dose toxicity study was diagnosed as a drug-induced autoimmune hemolytic anemia (AIHA) and the primary cause was assumed to be production of IgG class anti-erythrocyte autoantibodies.  (+info)

Autoimmune hemolytic anemia associated with benign ovarian cyst: a case report and review of literature. (66/384)

A 28-years-old female presented with severe autoimmune hemolytic anemia (AIHA), warm antibody mediated, and right side tubo-ovarian (TO) mass. There was sub-optimal response to immunosuppressive therapy (IST). Eight months later she underwent ovarian cystectomy which resulted in complete remission of AIHA without the need for IST. Pathological examination of the TO mass revealed benign ovarian cyst. Our case highlights the need to search for ovarian cyst/mass in females presenting with AIHA. Since immunosuppressive therapy is usually ineffectual in AIHA associated with ovarian cyst, it may be appropriate to contemplate surgery before embarking on IST in such cases.  (+info)

Erythropoietin gene therapy leads to autoimmune anemia in macaques. (67/384)

Gene therapy is being considered for the delivery of therapeutic proteins. We evaluated the delivery of the hormone erythropoietin (EPO) into cynomolgus macaques through intramuscularly administered adeno-associated virus (AAV) vectors. As expected, the animals developed supraphysiologic levels of EPO and polycythemia. However, severe anemia ensued in some animals because of an autoimmune response to endogenous and transgene derived EPO. This is the first example of gene therapy leading to inadvertent auto-immunity in primates.  (+info)

Autoimmune anemia in macaques following erythropoietin gene therapy. (68/384)

We delivered the homologous erythropoietin (Epo) cDNA driven from a doxycycline-regulated promoter via recombinant adeno-associated virus in skeletal muscle of 9 cynomolgus macaques. Upon induction, rapid supraphysiologic levels of Epo were obtained. Unexpectedly, some individuals developed a profound anemia that correlated with the appearance of neutralizing antibodies against the endogenous Epo. Both the endogenous erythropoietin and vector sequences were identical. This is the first example of the inadvertent development of an autoimmune disease in primates as a result of gene transfer of a gene expressing a self-antigen. It raises some concerns when a therapeutic protein is produced at high levels from an ectopic site.  (+info)

Post-liver-transplant anemia: etiology and management. (69/384)

Anemia is common after liver transplantation, with the incidence ranging from 4.3% to 28.2% depending on the criteria used to define anemia. The cause of anemia is unidentified in the majority of patients, and it is likely to be multifactorial. Immunosuppressive-medication-induced bone marrow suppression is perhaps the most common cause of unexplained anemia. Chronic blood loss, iron deficiency, hemolysis, and renal insufficiency are other potential causes of chronic anemia. Rare causes, somewhat unique to transplantation, include aplastic anemia, graft-versus-host disease (GVHD), and lymphoproliferative disease. Anemia due to immunosuppressive medication is challenging, since almost all drugs currently used for this purpose cause anemia, but the renal-sparing property of sirolimus may benefit the subgroup in which renal insufficiency is contributing to anemia. Aplastic anemia is seen in young patients transplanted for non-A, non-B, non-C, fulminant hepatic failure. It is thought to be immunologically mediated, secondary to an unknown viral infection, and is associated with a grave prognosis. GVHD is another infrequent (approximately 1% of transplant recipients) but serious cause of severe anemia that carries a dismal prognosis. Lymphoproliferative disorder, too may rarely rare cause anemia and it may respond to reduction of immunosuppression. Recipients of solid-organ transplants do not mount a significant increase in erythropoietin in response to anemia. In conclusion, though there are no data on the response of anemia to erythropoietin in liver transplant recipients, it appears to benefit other solid-organ-transplant recipients with anemia.  (+info)

Successful management of severe chronic autoimmune hemolytic anemia with low dose cyclosporine and prednisone in an infant. (70/384)

Autoimmune hemolytic anemia (AIHA) is characterized by shortened red cell survival due to the presence of autoantibodies directed against antigens on the red blood cell membrane. Corticosteroids and rarely intravenous immunoglobulin G are used in the treatment of AIHA. We report a six-month-old boy with severe AIHA who initially responded to high dose methylprednisolone (HDMP) and intravenous immunoglobulin G (IVIG) therapies but eventually became refractory. He was then treated with low dose cyclosporine and prednisone successfully. In conclusion low dose cyclosporine and prednisone should be kept in mind in severe IHA.  (+info)

Low-titer cold agglutinin disease with systemic sclerosis. (71/384)

A 60-year-old woman with systemic sclerosis (SSc) was admitted because of severe anemia and Raynaud's phenomenon. Her anemia was associated with a low serum haptoglobin level and positive results of direct Coomb's tests, which indicated the presence of autoimmune hemolysis. Other laboratory investigations revealed positive anti-nuclear antibodies, anti-topoisomerase antibody, cold agglutinins, as well as low serum levels of IgM, C3, C4 and CH50. Bone marrow aspiration showed discrete hyperplasia of the erythropoietic system. She was diagnosed as low-titer cold agglutinin disease rousing secondarily to SSc. The anemia was alleviated with the oral administration of prednisolone. This case emphasized, in terms of pathogenesis, the close association between systemic rheumatic diseases and hematological abnormalities evoked by autoimmunity.  (+info)

Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. (72/384)

Conventional therapies for primary chronic cold agglutinin disease (CAD) are ineffective, but remissions after treatment with the anti-CD20 antibody rituximab have been described in a small, prospective trial and in some case reports. In this study we report on 37 courses of rituximab administered prospectively to 27 patients. Fourteen of 27 patients responded to their first course of rituximab, and 6 of 10 responded to re-treatment. In both groups combined, responses were achieved after 20 of 37 courses, giving an overall response rate of 54%. We observed 1 complete and 19 partial responses. Two nonresponders and 3 patients who experienced relapse received second-line therapy with interferon-alpha combined with a new course of rituximab, and 1 nonresponder and 2 patients who experienced relapse achieved partial responses. Responders achieved a median increase in hemoglobin levels of 40 g/L (4 g/dL). Median time to response was 1.5 months, and median observed response duration was 11 months. We conclude that rituximab is an effective and well-tolerated therapy for CAD. Histologic and flow cytometric findings suggest that some of the effect may be mediated by mechanisms other than the elimination of clonal lymphocytes. We were unable to predict responses from the hematologic, immunologic, or histologic parameters before therapy.  (+info)