losartan-potassium and Autoimmune-Diseases

Immunogenicity of therapeutic proteins is a nightmare for industrials because induced antibodies can neutralize the therapeutic activity and provoke autoimmune symptoms. It was believed that sequence humanization would be sufficient to tackle these problems but multiple clinical examples now demonstrate that humanization does not suffice to abrogate immune responses. In order to predict immunogenicity of therapeutic proteins, different approaches have been developed, among which the most relevant ones are based on the evaluation of the response of naïve CD4 T lymphocytes specific for therapeutic proteins. Other approaches also exist or are in development. This review is the state of art in the different technologies that are proposed to predict immunogenicity of therapeutic proteins.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Chimera; Drug Resistance; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunization; Immunologic Tests; Isoantibodies; Lymphocyte Activation; Mice; Mice, Transgenic; Models, Immunological; Proteins; Recombinant Proteins

Rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B cells and mature B cells (but not on plasma cells), was introduced in the late 1990s for the treatment of non-Hodgkin's lymphoma. Recently, this antibody has been used to treat autoimmune diseases, especially those associated with a prominent humoral component and with potentially pathogenic autoantibodies. Small cohort studies have indicated that rituximab could have an important role in the management of these disorders. Rituximab has also been utilized in the transplant setting, to diminish levels of alloreactive antibodies in highly sensitized patients, to manage ABO-incompatible transplants, and to treat rejection associated with B cells and antibodies. The exact mechanism by which rituximab exerts its effects in autoimmunity and transplantation remains unclear, as specific autoantibody or alloantibody levels often seem not to diminish in parallel with clinical improvement. A role for rituximab in depleting B cells and compromising their antigen-presenting function seems likely; rituximab might also inhibit T-cell activation. A synergistic effect has been noted in vitro following administration of corticosteroids to B-cell lines, with accentuation of B-cell cytotoxicity; this observation might be relevant to certain studies, as some regimens have utilized both agents simultaneously. This article reviews the current use of rituximab in renal disease and transplantation, and includes discussion of the drug's potential role in novel therapeutic protocols.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Erythropoietin; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Immunologic Factors; Kidney Diseases; Kidney Transplantation; Lupus Erythematosus, Systemic; Lymphoproliferative Disorders; Recombinant Proteins; Red-Cell Aplasia, Pure; Rituximab; Vasculitis

The importance of recombinant human erythropoietin (epoetin) therapy has been clearly demonstrated in patients with anemia due to chronic kidney disease. The use of biopharmaceuticals to replace endogenous proteins, which may be inadequately low, carries the risk of stimulating the immune system to develop autoantibodies. Although these proteins are designed to closely mimic the endogenous proteins, they may have potential immunogenic properties. Erythropoietin produced by recombinant DNA technology is the most successful and efficacious agent for treating anemia. It was initially used in treating anemia in chronic kidney disease patients. Pure red cell aplasia (PRCA) ensuing from production of neutralizing anti-erythropoietin antibodies occurred very rarely with epoetin treatment. This agent was initially administered intravenously, but the mode of administration was progressively altered to subcutaneous without apparent increase in immune reaction. However, between 1998 and 2001, a sharp increase in the number of PRCA cases was seen. PRCA had been a very rare complication until this time. All of these patients had high affinity neutralizing anti-erythropoietin antibodies. This observation was made primarily in cases where one brand of epoetin, Eprex, was administered subcutaneously to patients with chronic kidney disease treated outside the United States, although a small number of cases among chronic kidney disease patients treated solely with epoetin beta were also identified. The marked increase in the number of Eprex cases was attributed to a change in the stabilizers, storage, and route of administration of Eprex to patients with chronic kidney disease. Since then changes have been made to the route of administration, storage, and handling of Eprex, and more recently to the rubber stoppers used in the prefilled syringes. Eprex was administered intravenously to chronic kidney disease patients and, with improved storage and handling, there was a subsequent dramatic reduction in the number of cases. More recently, the rubber stoppers have been replaced by Teflon-coated ones to prevent interactions with stabilizers and release of chemicals that have adjuvant properties. However, this concern is still relevant in the new generation of epoetin agents and generic formulations of epoetins. Epoetin treatment for anemia requires regular follow-up of hemoglobin levels but also of reticulocyte counts in chronic kidney disease patients.

Topics: Anemia; Antibodies; Autoimmune Diseases; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

During the first 10 yr of therapy with recombinant human erythropoietin ([EPO]), only three cases of antibody-associated pure red cell aplasia have been described in patients who were treated with EPO, whereas several millions of patients have received this treatment. Thus, the possibility for epoetin to induce the formation of anti-EPO antibodies was considered extremely low. However, since 1998, a significant increase in the number of cases of EPO-induced pure red cell aplasia has been found in patients with chronic kidney disease with a peak in 2001 and 2002. The incidence rate seems now to be back to the baseline level. The change in formulation of epoetin a sold outside the United States seems to be the cause of these antibodies.

Topics: Autoimmune Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Humans; Incidence; Male; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment

Acquired pure red cell aplasia (PRCA) is a rare condition. Traditionally it has been described in association with various etiologies such as parvovirus B19 infection, auto-immune disorders and drugs. Immunologically mediated PRCA is by far the commonest cause in adults, particularly since 1998, when a marked increased incidence of PRCA was noted in chronic renal failure patients receiving subcutaneous (SC) recombinant erythropoietin (rEpo). Typically these patients had been given erythropoietin for correction of anemia of renal failure and subsequently present with severe transfusion dependent anemia. Most cases were associated with SC administration of human serum albumin (HSA) free erythropoieitin alfa product (Eprex). Early recognition and withdrawal of erythropoietin therapy is essential. Treatment with immunosuppressive therapy, particularly in conjunction with renal transplant results in good response with resolution in the majority of cases. The pathogenesis is related to interaction of multiple factors such as formulation change and improper storage leading to increased immunogenicity of the recombinant product. The incidence peaked in 2001 and 2002, subsequently dropping considerably from 2003. This can be explained by the institution of measures such as more stringent handling and storage conditions, improvements in formulation of HSA free Eprex and switch to intravenous (IV) administration for Eprex in dialysis patients. The evidence to date on this condition is summarized in this review.

Topics: Autoimmune Diseases; Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Failure, Chronic; Parvoviridae Infections; Parvovirus; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases; Chemistry, Pharmaceutical; Drug Contamination; Epoetin Alfa; Erythropoietin; Europe; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors; Sorbitol; Treatment Outcome

Topics: Anemia; Autoimmune Diseases; Cell Hypoxia; Disease-Free Survival; Double-Blind Method; Erythropoietin; Heart Failure; Humans; Kidney; Kidney Diseases; Lymphoma, Non-Hodgkin; Multiple Myeloma; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Erythropoietin (EPO) is a 165 amino-acid sequence glycoprotein which plays an important role in maintaining regular generation of erythrocytes, Jacobs et al. describe the cloning of the human EPO and recombinant EPO has been introduced for the treatment of anemia in patients with renal diseases. The extensive utilization of EPO can induce the production of neutralizing EPO antibodies, which have been proved in patients with the non-infectious form of pure red cell aplasia (NI-PRCA), an autoimmune disease characterized by a sudden inhibition of erythrocyte maturation and production. In this review, the literature concerning the molecular structure and the genetic profile of EPO as well as the relationship between neutralizing EPO antibodies and NI-PRCA have been analyzed.

Topics: Anemia; Animals; Autoantibodies; Autoimmune Diseases; Epitopes; Erythropoietin; Glycosylation; Growth Substances; Humans; Isoantibodies; Protein Conformation; Protein Processing, Post-Translational; Rabbits; Recombinant Proteins; Red-Cell Aplasia, Pure

Erythropoietin and its receptor function as primary mediators of the normal physiological response to hypoxia. Erythropoietin is recognized for its central role in erythropoiesis, but studies in which recombinant human erythropoietin (epoetin alfa) is injected directly into ischaemic rodent brain show that erythropoietin also mediates neuroprotection. Abundant expression of the erythropoietin receptor has been observed at brain capillaries, which could provide a route for circulating erythropoietin to enter the brain. In confirmation of this hypothesis, systemic administration of epoetin alfa before or up to 6 h after focal brain ischaemia reduced injury by 50-75%. Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate. Thus, systemically administered epoetin alfa in animal models has neuroprotective effects, demonstrating its potential use after brain injury, trauma and multiple sclerosis. It is evident that erythropoietin has biological activities in addition to increasing red cell mass. Given the excellent safety profile of epoetin alfa, clinical trials evaluating systemically administered epoetin alfa as a general neuroprotective treatment are warranted.

Topics: Acute Disease; Animals; Autoimmune Diseases; Brain; Brain Ischemia; Cerebral Cortex; Encephalitis; Epoetin Alfa; Erythropoietin; Humans; Kainic Acid; Neuroprotective Agents; Recombinant Proteins; Stroke; Wounds, Nonpenetrating

Immune-mediated acquired disorders of erythropoiesis can result in pure red cell aplasia or ineffective erythropoiesis. Erythropoiesis can be suppressed or impaired by humoral or cellular mechanisms. In vitro inhibition of erythroid colony growth by humoral factors or lymphocytes is a strong argument for the immune origin of the disease. Classical aetiologies are thymoma and hematological malignancies such as chronic lymphocytic leukaemia. Clonal proliferation of T cells has also been incriminated. Recently, acquired circulating autoantibodies directed against erythropoietin have been detected in a case of pure red cell aplasia. Autoimmune mechanisms have also been suggested in two dyserythropoietic syndromes recently described.

Topics: Anemia; Autoimmune Diseases; Cell Division; Erythropoiesis; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Red-Cell Aplasia, Pure; T-Lymphocytes; Thymoma

Topics: Acquired Immunodeficiency Syndrome; Autoimmune Diseases; Erythropoietin; Humans; Hypertension; Neoplasms

Topics: Anemia; Anemia, Aplastic; Antibodies, Anti-Idiotypic; Antigen-Antibody Complex; Autoimmune Diseases; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Chromium Radioisotopes; Complement System Proteins; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Heme; Humans; Immunoglobulin G; Immunosuppressive Agents; Iron; Iron Radioisotopes; Middle Aged

To explore the possible pathogenetic role of erythropoietin (EPO) in the anaemia associated with cyclosporin (Cs) in newly diagnosed patients with insulin-dependent diabetes mellitus (IDDM).. A multicentre randomized placebo controlled prospective trial of Cs immunosuppression for 12 months in IDDM patients.. Patients were recruited from the out-patient clinics of diabetes centres in Europe and Canada.. Patients 9-35 years old with a clinical diagnosis of ketonuric IDDM entering less than 6 weeks after diagnosis. 188 patients were originally recruited; 105 patients completed the investigation, 52 patients being treated with Cs, and 53 patients receiving placebo.. Random allocation to receive either Cs or placebo. The initial dose of Cs was 10 mg kg-1 BW day-1. Therapy was maintained for 12 months.. B-Haemoglobin, s-creatinine, and s-EPO concentrations were monitored before, during and after therapy with either Cs or placebo.. Blood-haemoglobin (Hgb) fell from 8.5 +/- 0.8 to a nadir of 7.8 +/- 0.9 mmol l-1 at 6 months (P < 0.0001) in IDDM patients treated with Cs but not in the placebo patients (8.5 +/- 0.8 to 8.8 +/- 0.9 mmol l-1, NS). The mean serum EPO levels remained unaltered throughout the 6-month period of Cs and placebo therapy. No significant differences in serum EPO levels between Cs and placebo-treated diabetic patients were found after 6 months of treatment.. The light anaemia associated with Cs therapy in IDDM patients is not related to an insufficient production of EPO, but is caused by other, as yet unknown mechanisms, unrelated to the nephrotoxic action of this drug.

Topics: Adolescent; Adult; Anemia; Autoimmune Diseases; Child; Cyclosporine; Diabetes Mellitus, Type 1; Double-Blind Method; Erythropoietin; Follow-Up Studies; Humans; Prospective Studies; Time Factors

Patients with chronic kidney disease (CKD) frequently suffer from heart disease as well. The combination of the two processes can exacerbate inflammation, resulting in increases in both resistance to erythropoietin (EPO) and mortality.. The aim of this study was to determine the prevalence of heart disease in a representative group of non-dialysis patients with stage 4-5 CKD, and the influence of that entity on EPO requirements and on mortality during a period of 36 months.. 134 patients (68% on EPO at the beginning, increasing to 72.3% during follow-up) were monitored for 36 months. To evaluate the dose-response effect of EPO therapy, we used the erythropoietin resistance index (ERI) calculated as the weekly weight-adjusted dose of EPO divided by the haemoglobin level. The ERI was determined both initially and during the last six months before the end of the study.. 39 patients (29.1%) had history of heart disease; 22 (16.4%) had suffered from heart failure (HF). The ERI was higher in patients with a history of heart disease or HF and those treated with drugs acting on the renin-angiotensin system (ACE inhibitors or ARBs). Using ERI as the dependent variable in the multivariate analysis, the variables that composed the final model were ferritin, haemoglobin, glomerular filtration rate and history of HF. The 36 month mortality rate (n=39 patients) was higher in the group having ERI above the median (2.6IU/week/kg/gram of haemoglobin in 100ml) (P=.002), and in the groups with heart disease (P=.001) or HF (P=.001) according to the Kaplan-Meier survival analysis.. Patients with history of heart disease or HF have a higher ERI, and all of these characteristics are associated with lower survival. ERI can be considered a marker for risk of death in the short to-medium term.

Topics: Aged; Aged, 80 and over; Anemia; Autoimmune Diseases; Cardio-Renal Syndrome; Cardiovascular Agents; Comorbidity; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Resistance; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Heart Diseases; Heart Failure; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Severity of Illness Index

Autoimmune hyperlipidemia (AIH) is a rare cause of secondary hyperlipidemia. A few cases of AIH have been reported in multiple myeloma.. A female in her fifties was referred to the outpatient clinic presenting with headache, blurred vision and skin rash. Physical examination with subsequent laboratory and histological examinations revealed severe hyperlipidemia secondary to secretory multiple myeloma with monoclonal IgG kappa protein and erythrocytosis secondary to a erythropoietin secreting adenoma in the liver.. Treatment for multiple myeloma (induction treatment and autologous hematological stem cell transplantation) gained partial remission and was associated with normalization of serum lipids. There was no need for further medical treatment of the hyperlipidemia. Three years after the initial treatment, serum concentrations of triglycerides and total cholesterol increased in parallel with monoclonal IgG kappa protein. Total cholesterol and triglycerides decreased and remained within the reference ranges after retreatment with a second autologous stem cell transplantation. Surgical removal of the hepatic adenoma caused normalisation of the erythropoietin concentration and resolution of the erythrocytosis. The present case reports two rare complications (AIH and erythrocytosis) to multiple myeloma and hepatic adenoma, with regression of complaints and normalisation of laboratory tests after adequate treatment of underlying diseases.

Topics: Adenoma, Liver Cell; Antibodies, Monoclonal; Anticholesteremic Agents; Antineoplastic Agents; Autoimmune Diseases; Erythropoietin; Fatty Acids, Omega-3; Female; Humans; Hyperlipidemias; Immunoglobulin A; Immunosuppressive Agents; Liver Neoplasms; Middle Aged; Multiple Myeloma; Polycythemia

Dilated human cardiomyopathy is associated with suppression of the prosurvival phosphatidylinositol-3-kinase (PI3K)/Akt and STAT3 pathways. The present study was carried out to determine if restoration of the PI3K/Akt and STAT3 activity by darbepoetin alfa improved cardiac function or reduced cardiomyocyte apoptosis in rabbit autoimmune cardiomyopathy induced by a peptide corresponding to the second extracellular loop of the ss(1)-adrenergic receptor (ss(1)-EC(II)). We found that ss(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction and myocyte apoptosis as measured by TUNEL, single-stranded DNA antibody, and active caspase-3. These changes were associated with activation of p38 mitogen-activated protein kinase (MAPK), endoplasmic reticulum stress markers (GRP78 and CHOP), and increased cleavage of procaspase-12, as well as decreased phosphorylation of Akt and STAT3, and decreased Bcl2/Bax ratio. As expected, darbepoetin alfa treatment increased phosphorylation of Akt and STAT3. It also increased the myocardial expression of erythropoietin receptor which was reduced in the failing myocardium, and improved cardiac function in the ss(1)-EC(II)-immunized animals. The latter was associated with reductions of myocyte apoptosis and cleaved caspase-3, as well as reversal of increased phosphorylation of p38-MAPK, increased ER stress, and decline in Bcl2/Bax ratio. The anti-apoptotic effects of darbepoetin alfa via Akt and STAT activation were also demonstrated in cultured cardiomyocytes treated with the anti-ss(1)-EC(II) antibody. These effects of darbepoetin alfa in vitro were prevented by LY294002 and STAT3 peptide inhibitor. Thus, we conclude that darbepoetin alfa improves cardiac function and prevents progression of dilated cardiomyopathy probably by activating the PI3K/Akt and STAT3 pathways and reducing ER stress.

Topics: Animals; Animals, Newborn; Autoimmune Diseases; Cardiomyopathy, Dilated; Cardiotonic Agents; Cells, Cultured; Darbepoetin alfa; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Erythropoietin; Humans; Myocytes, Cardiac; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rabbits; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor

Beneficial effects of short-term erythropoietin (EPO) therapy have been demonstrated in several animal models of acute neurologic injury, including experimental autoimmune encephalomyelitis (EAE)--the animal model of multiple sclerosis. We have found that EPO treatment substantially reduces the acute clinical paralysis seen in EAE mice and this improvement is accompanied by a large reduction in the mononuclear cell infiltration and downregulation of glial MHC class II expression within the inflamed CNS. Other reports have recently indicated that peripherally generated anti-inflammatory CD4(+)Foxp3(+) regulatory T cells (Tregs) and the IL17-producing CD4+ T helper cell (Th17) subpopulations play key antagonistic roles in EAE pathogenesis. However, no information regarding the effects of EPO therapy on the behavior of the general mononuclear-lymphocyte population, Tregs or Th17 cells in EAE has emerged.. We first determined in vivo that EPO therapy markedly suppressed MOG specific T cell proliferation and sharply reduced the number of reactive dendritic cells (CD11c positive) in EAE lymph nodes during both inductive and later symptomatic phases of MOG(35-55) induced EAE. We then determined the effect in vivo of EPO on numbers of peripheral Treg cells and Th17 cells. We found that EPO treatment modulated immune balance in both the periphery and the inflamed spinal cord by promoting a large expansion in Treg cells, inhibiting Th17 polarization and abrogating proliferation of the antigen presenting dendritic cell population. Finally we utilized tissue culture assays to show that exposure to EPO in vitro similarly downregulated MOG-specific T cell proliferation and also greatly suppressed T cell production of pro-inflammatory cytokines.. Taken together, our findings reveal an important new locus whereby EPO induces substantial long-term tissue protection in the host through signaling to several critical subsets of immune cells that reside in the peripheral lymphatic system.

Topics: Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Central Nervous System; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Forkhead Transcription Factors; Genes, MHC Class II; Inflammation; Interleukin-17; Leukocytes, Mononuclear; Lymph Nodes; Mice; Mice, Inbred C57BL

Erythropoietin (EPO) has been shown to not only have cardioprotective effects but also attenuate autoimmune diseases. In the present study, we investigated the effect of EPO on cardiac inflammation and function, inflammatory cell infiltration, and cytokine expression in a rat model of experimental autoimmune myocarditis (EAM).. Male Lewis rats (6-8 weeks old) were immunized on day 0 with porcine cardiac myosin to establish EAM. The rats were subcutaneously administered either vehicle (saline) or human recombinant EPO (6,000 U/kg, 3 days/week) from day 0 to 20, and they were evaluated on day 21. In the EPO group, the inflammation area and heart weight/body weight ratio were significantly attenuated as compared with those in the vehicle group. Blood pressure and cardiac function were also improved in the EPO group. Immunohistochemistry revealed that EPO decreased the infiltration of macrophages and CD4 T cells, and degranulated mast cells in the myocardium. Real-time RT-PCR analysis demonstrated that inflammatory cytokine expression in the myocardium and lymphocytes was suppressed in the EPO group. However, in vitro experiments showed that EPO had no effect on antigen-induced proliferation and cytokine expression in lymphocytes.. EPO attenuates inflammatory cell infiltration and cytokine expression, and it improves cardiac function and reduces cardiac inflammation in EAM. This beneficial effect of EPO is unlikely to arise from a direct anti-inflammatory action on lymphocytes. These findings suggest the therapeutic potential of EPO for the treatment of myocarditis.

Topics: Animals; Animals, Newborn; Autoimmune Diseases; Blood Pressure; Blotting, Western; Cardiac Myosins; Cells, Cultured; Chemokine CCL2; Cytokines; Erythropoietin; Hemoglobins; Immunochemistry; Macrophages; Male; Mast Cells; Models, Animal; Myocarditis; Myocytes, Cardiac; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; Spleen; Ventricular Function, Left

Many possible causes of resistance to human recombinant erythropoietin (rh-EPO) have been reported in patients with renal failure. This case presents an unusual cause of erythropoietin-resistant anemia in a patient with chronic renal failure. A 61-year-old male patient who was on chronic hemodialysis program due to diabetic nephropathy for seven months developed erythropoietin resistant anemia. No iron deficiency was revealed by laboratory data, no megaloblastic anemia were found by biochemical investigation, and no inflammatory states including infection or neoplastic diseases were disclosed by abdominal ultrasonography, chest X-ray, bone marrow aspiration and biopsy, or other methods (normal C-reactive protein levels). This hemodialysis patient had epoetin-resistant anemia with primary autoimmune hyperthyroidism. The anti-thyroid therapy was effective not only against the hyperthyroidism but also against his epoetin resistant anemia.

Topics: Anemia; Antithyroid Agents; Autoimmune Diseases; Drug Resistance; Erythropoietin; Humans; Hyperthyroidism; Kidney Failure, Chronic; Male; Methimazole; Middle Aged; Recombinant Proteins; Renal Dialysis

Erythropoietin (EPO) has been known to have cytoprotective effects on several types of tissues, presumably through modulation of apoptosis and inflammation. The effect of EPO on myocardial inflammation, however, has not yet been clarified. We investigated the cardioprotective effects of EPO in rats with experimental autoimmune myocarditis (EAM). Seven-week-old Lewis rats immunized with cardiac myosin were treated either with EPO or vehicle and were examined on day 22. EPO attenuated the functional and histological severity of EAM along with suppression of mRNAs of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in the hearts as well as a reduction of apoptotic cardiomyocytes. The EPO receptor (EPO-R) was upregulated in the myocardium of EAM compared with that of healthy rats. These results may suggest that EPO ameliorated the progression of EAM by modulating myocardial inflammation and apoptosis.

Topics: Animals; Apoptosis; Autoimmune Diseases; Cardiotonic Agents; Cytokines; Erythropoietin; Humans; Male; Myocarditis; Rats; Rats, Inbred Lew; Recombinant Proteins; Treatment Outcome

The association between myelodysplastic syndromes (MDS) and autoimmune manifestations is not uncommon. As a rule, autoimmune abnormalities follow the diagnosis of MDS. We describe here a patient with MDS who developed a striking spectrum of diverse autoimmune disorders, including dermatitis, polyarthritis, and vasculitis, which preceded the clinical appearance of MDS.

Topics: Aged; Aged, 80 and over; Arthritis; Autoimmune Diseases; Blood Transfusion; Combined Modality Therapy; Dermatitis; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Filgrastim; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Methylprednisolone; Myelodysplastic Syndromes; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vasculitis

Epoetin alfa (Eprex*; Johnson & Johnson, Manati, PR) has been used successfully to correct the anemia of chronic renal failure for more than 12 years. Anti-erythropoietin (anti-EPO) antibodies have been reported in a small number of patients, resulting in a blood disorder, pure red cell aplasia (PRCA). To evaluate the utility of a large-scale anti-EPO antibody screening program in patients with chronic kidney disease (CKD) administered epoetin alfa, a study involving 5 large renal centers in southern Ontario, Canada, was conducted.. More than 1,500 hemodialysis, peritoneal dialysis, and predialysis patients were screened for the prevalence of anti-EPO antibodies by means of a radioimmunoprecipitation (RIP) assay. Serum samples were drawn and shipped to PPD Development (Richmond, VA) for the immunoprecipitation assay. Serum EPO levels also were measured. All samples that tested positive or borderline for antibodies were sent to MDS Pharma Services (Montreal, Canada) for the neutralization assay.. Of 1,531 samples tested, 1 patient tested low-positive and 3 borderline results were detected by means of RIP. PRCA previously was diagnosed in the patient with the low-positive antibody level; the patient was treated with cyclosporine and currently is being administered epoetin alfa with good response. The 3 patients with borderline antibody results manifested no clinical signs of PRCA. Neutralization assays performed on all 4 serum samples were negative for anti-EPO antibodies.. Results from this surveillance study show that the prevalence of antibody to EPO in patients with CKD administered epoetin alfa in 5 Canadian renal centers is low, and the value of a large-scale antibody screening program for PRCA cannot be justified.

Topics: Aged; Aged, 80 and over; Anemia; Autoantibodies; Autoimmune Diseases; Cross-Sectional Studies; Cyclosporine; Epoetin Alfa; Erythropoietin; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Mass Screening; Middle Aged; Ontario; Peritoneal Dialysis; Population Surveillance; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Anemia; Autoimmune Diseases; Clinical Trials as Topic; Doping in Sports; Erythropoietin; Humans; Kidney Diseases; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome; Uremia

Topics: Autoantibodies; Autoimmune Diseases; Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Adult; Autoantibodies; Autoimmune Diseases; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Immunoglobulin G; Infant, Newborn; Isoantibodies; Red-Cell Aplasia, Pure; Risk; Safety

Topics: Anemia, Hypochromic; Antirheumatic Agents; Autoimmune Diseases; Blood Loss, Surgical; Christianity; Crohn Disease; Erythropoietin; Folic Acid Deficiency; Hepatitis C, Chronic; Hip Fractures; Humans; Iron; Male; Middle Aged; Paraproteinemias; Premedication; Proteus Infections; Recombinant Proteins; Spondylitis, Ankylosing; Sulfasalazine; Urinary Tract Infections; Vitamins

A 35-year-old female presented with isolated thrombocytopenia of autoimmune origin. One and a half years later, hypoplastic myelodysplastic (MDS) was diagnosed. Following treatment with cyclosporin A, erythropoietin and granulocyte colony-stimulating factor, the patient has achieved a sustained hematological remission which is still ongoing after 3 years. Furthermore, to the best of our knowledge, this is the third case described in the literature where treatment with cytokines alone or in combination with immunosuppressive agents has resulted in a long standing cytogenetic response in MDS.

Topics: Adult; Autoimmune Diseases; Cyclosporine; Disease Progression; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Platelet Count; Remission Induction; Thrombocytopenia

Topics: Aged; Anemia; Anti-Inflammatory Agents; Autoimmune Diseases; Drug Resistance; Erythropoietin; Female; Humans; Male; Prednisolone; Recombinant Proteins; Renal Dialysis

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Autoimmune Diseases; Blood Donors; Erythropoietin; Hematologic Diseases; Humans; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins

To assess the efficacy and the mechanism of action of alpha-interferon (alpha-IFN) in the treatment of HIV-related thrombocytopenia.. Thirteen HIV-positive subjects [nine men and four women with severe thrombocytopenia (platelets, < or = 30 x 10(9)/l)] were treated with alpha-IFN 2b alone at a dose of 3 x 10(6) U three times a week for 5 weeks. Haematological parameters, platelet kinetic and bone-marrow myeloid progenitor cultures [megakaryocyte colony-forming units (CFU-MK); granulocyte macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E)] were evaluated before and after treatment in responsive subjects.. Seven out of 13 subjects showed a partial response (platelets, 50-149 x 10(9)/l) after alpha-IFN 2b therapy. Platelet survival as evaluated by 111In-oxine significantly increased, while platelet turnover showed a slight but not statistically significant increase after treatment. The growth of bone-marrow myeloid progenitor cells decreased after alpha-IFN 2b therapy, again without statistical significance.. alpha-IFN 2b may increase the platelet count in HIV-positive subjects with severe symptomatic thrombocytopenia by prolonging platelet survival. The immunomodulatory and antiviral action of this drug may be responsible for prolonged platelet survival.

Topics: Adult; AIDS-Related Complex; Autoimmune Diseases; Cell Survival; Cells, Cultured; Colony-Forming Units Assay; Drug Evaluation; Erythroid Precursor Cells; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Humans; Interferon alpha-2; Interferon-alpha; Interleukin-3; Male; Megakaryocytes; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Thrombocytopenia

Topics: Autoimmune Diseases; Drug Resistance; Erythropoietin; Female; Humans; Methylprednisolone; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission Induction

Topics: Autoimmune Diseases; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Immunization, Passive; Immunoglobulin G; Immunoglobulins, Intravenous; Infant; Injections, Intravenous; Red-Cell Aplasia, Pure

A case of adult pure red cell aplasia (PRCA) with a serum IgG inhibitor to erythropoiesis and an IgG lambda M component is presented. The study of lymphocyte populations revealed a slight but definite decrease of E and EA rosettes, with dissociation between E rosettes and PHA blastic transformation of blood lymphocytes and increase of membrane IgM-bearing lymphocytes. The relationship between PRCA and paraproteinemia is discussed: it is suggested that the serum M component may derive from an immunological unbalance between T and B lymphocytes. Since a survey of the literature reveals 5 similar cases, it is suggested that paraproteinemia may be the hallmark of a particular variety of chronic PRCA 'type 1'.

Topics: Aged; Anemia, Aplastic; Autoimmune Diseases; Erythropoietin; Female; Fluorescent Antibody Technique; Humans; Immunoglobulin G; Lymphocytes; Paraproteinemias; Receptors, Antigen, B-Cell; Rosette Formation

Two experimental models for pure red cell aplasia (PRCA) were established. In the first one, administration of PRCA serum IgG in normal mice induced a sustained inhibitory effect on erythropoiesis, a progressive decline of the hematocrit values and an inverse rise of erythropoietin (Ep) levels in serum. Thus, the physiopathological pattern of PRCA type I (or A) was established, In the second model a rabbit producing anti-Ep crossreacting with endogenous Ep was subjected to a booster injection of Ep. The rise of the immune response was associated with decrease of Gct values and disappearance of erythroid precursors from marrow smears, and its subsequent decline with reticulocytosis and regression of the anemia, thus reproducing the physiopathological pattern of PRCA type II (or B).

Topics: Anemia, Aplastic; Animals; Autoantibodies; Autoimmune Diseases; Chronic Disease; Disease Models, Animal; Erythropoietin; Immune Sera; Immunoglobulin G; Mice; Rabbits

Topics: Adult; Animals; Antibodies; Antibodies, Antinuclear; Autoimmune Diseases; Binding Sites; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Female; Hematocrit; Heme; Hemoglobinometry; Humans; Immune Sera; Immunoglobulin G; In Vitro Techniques; Iron Isotopes; Leukocyte Count; Mice; Myasthenia Gravis; Purpura, Thrombocytopenic; Rats; Reticulocytes; Rheumatoid Factor

Topics: Animals; Autoimmune Diseases; Bone Marrow Diseases; Erythropoiesis; Erythropoietin; Female; gamma-Globulins; Humans; Mice; Middle Aged; Nucleoproteins