Erythropoietin in the intensive care unit: beyond treatment of anemia

Erythropoietin (EPO) is the major hormone stimulating the production and differentiation of red blood cells. EPO is used widely for treating anemia of critical illness or anemia induced by chemotherapy. EPO at pharmacological doses is used in this setting to raise hemoglobin levels (by preventing the apoptosis of erythroid progenitor cells) and is designed to reduce patient exposure to allogenic blood through transfusions. Stroke, heart failure, and acute kidney injury are a frequently encountered clinical problem. Unfortunately, in the intensive care unit advances in supportive interventions have done little to reduce the high mortality associated with these conditions. Tissue protection with EPO at high, nonpharmacological doses after injury has been found in the brain, heart, and kidney of several animal models. It is now well known that EPO has anti-apoptotic effects in cells other than erythroid progenitor cells, which is considered to be independent of EPOs erythropoietic activities. This review article summarizes what is known in preclinical models of critical illness and discusses why this does not correlate with randomized, controlled clinical trials

Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes

BACKGROUND: Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a meta-analysis of controlled ESA oncology trials to examine whether ESA use affects survival, disease progression and risk of venous-thromboembolic events

Tumor-induced tumor necrosis factor production in macrophages

Tumor-associated tumor necrosis factor (TNF) production in patients as well as a TNF-inducing membrane constituent of tumor cells have been reported. In a murine fibrosarcoma model we analyzed TNF production during growth of a tumor transplant. In situ hybridization showed that a gradually increasing number of cells within the tumor tissue became positive for TNFmRNA. Also, in spleen cells of tumor-bearing mice TNFmRNA became more abundant in later stages of tumor growth compared to early stages. In plasma of these animals, however, TNF activity was not detected at any time even after stimulation with bacterial endotoxin. Neutralization with monoclonal antibodies of endogenous TNF during tumor growth did not affect the growth rate of the tumor, indicating that either the antibodies did not reach the relevant TNF production and action sites or that endogenously produced TNF did not play a significant role in this tumor model

A common epitope on human tumor necrosis factor alpha and the autoantigen 'S-antigen/arrestin' induces TNF-alpha production

A common epitope on S-antigen (arrestin), a potent autoantigen inducing experimental autoimmune uveoretinitis (EAU), and on human tumor necrosis factor alpha (hTNF alpha) was revealed using two monoclonal antibodies to S-antigen which inhibit EAU induction. The minimal common sequence for monoclonal antibody recognition is GVxLxD in the S-antigen/hTNF alpha amino acid sequences. Peptides containing this sequence motif exhibited monocyte activating capacity similar to the autocrine stimulatory capacity of hTNF alpha itself. In the S-antigen this activity was located from residue 40 to 50, corresponding to the peptide PVDGVVLVDPE (epitope S2). In hTNF alpha, the monocyte activating capacity correlated to residue 31 to 53, corresponding to the peptide RRANALLANGVELRDNQLVVPSE (peptide RRAN). The identified regions define common functional structures in the autoantigen and in the hTNF alpha molecule. The data suggest a regulatory function of this particular structure in TNF alpha expression and in autoimmunity

Cytokine induction by immunomodulatory epitopes in S-antigen and tumor necrosis factor alpha

Common epitopes on S-antigen (arrestin), a potent autoantigen inducing experimental autoimmune uveoretinitis (EAU), and on human tumor necrosis factor alpha (hTNF alpha) are revealed with monoclonal antibodies (mAb) to S-antigen, which inhibit EAU induction. The minimal common sequence for mAb recognition is GVxLxD in the S-antigen/hTNF alpha amino acid (aa) sequences. Peptides containing this sequence motif exhibit monocyte activating capacity analogous to the autocrine stimulatory capacity of hTNF alpha itself. In S-antigen this activity is located at epitope S2 (aa residues 40 to 50), corresponding to the peptide PVDGVVLVDPE (peptide S2). In hTNF alpha the monocyte activating capacity correlates to aa residue 31 to 53, corresponding to the peptide RRANALLANGVELRDNQLVVPSE (peptide RRAN). Peptide S2 but not peptide RRAN is competing for mAbs S6H8 and S2D2 binding to S-antigen. Anti-idiotypic antibodies to S2D2 compete with peptide S2 but not peptide RRAN for binding to mAbs S2D2 and S6H8. In human retinal S-antigen epitope S2 is localized at the aa residues 44-54 and is cleaved in the human peptide 4 (aa 31-50). Competition experiments with peptide 4 (aa 31-50) and peptide 5 (aa 41-60) indicate that the C-terminal aa residues VDPD in the epitope S2 play an important role for internal image recognition of the anti-idiotypic antibodies. Peptide S2 and peptide RRAN define common functional structures in the autoantigen and hTNF alpha molecules. The data suggest regulatory functions of the peptides in cytokine expression, network regulation and in autoimmunity

Characterization of monocyte-activating tumour cell membrane structures

Tumor cells are known to activate monocytes/macrophages and it has been shown that this stimulation was conferred by tumour-cell membranes. In order to analyse the relevant structures for tumor cell-specific TNF-induction monocytes from healthy donors were cultured in the presence of plasma membrane preparations from Jurkat or K562 cells. Both tumour cell lines revealed a monocyte-stimulating plasma membrane component of about 45 kDa. The TNF-inducing factor exhibited characteristics of a glycoprotein with the carbohydrate moiety as the structure responsible for stimulation. CD2, a glycosylated T-cell specific membrane component, was identified as being involved in monocyte activation in the case of the Jurkat cells whereas the identity of the activating structure on K562 cells is still unknown. From the data presented here indicating the importance of carbohydrate structures for monocyte activation we conclude that altered glycosylation of cell surface molecules of tumour cells might be responsible for tumour cell-induced monocyte stimulation