Erythropoietin enhances immune responses in mice

Abstract

Erythropoietin (Epo) is the main erythropoietic hormone. Recombinant human Epo (rHuEpo) is thus used in clinical practice for the treatment of anemia. Accumulating data reveals that Epo exerts pleiotropic activities. We have previously shown an antineoplastic activity of Epo in murine multiple myeloma (MM) models, and in MM patients. Our findings that this anti-neoplastic effect operates via CD8 + T lymphocytes led us to hypothesize that Epo possesses a wider range of immunomodulatory functions. Here we demonstrate the effect of Epo on B lymphocyte responses, focusing on three experimental models: (i) tumor-bearing mice, (5T2 MM mouse); (ii) antigen-injected healthy mice; and (iii) antigen-injected transgenic mice (tg6), overexpressing human Epo. In the MM model, despite bone marrow dysfunction, Epo-treated mice retained higher levels of endogenous polyclonal immunoglobulins, compared to their untreated controls. In both Epo-treated wild type and tg6 mice, Epo effect was manifested in the higher levels of splenocyte proliferative response induced in vitro by lipopolysaccharide. Furthermore, these mice had increased in vivo production of anti-dinitrophenyl (DNP) antibodies following immunization with DNP-keyhole limpet hemocyanin. Epo-treated mice showed an enhanced immune response also to the clinically relevant hepatitis B surface antigen. These findings suggest a potential novel use of rHuEpo as an immunomodulator.See accompanying commentary: http://dx.doi. org/10.1002/eji.200737401 Introduction Erythropoietin (Epo), produced mainly in the adult kidney, is the major growth regulator of the erythroid cell lineage. Cloning of the Epo gene has led to the introduction of recombinant human Epo (rHuEpo) into clinical practice as a treatment for various anemias, including anemia related to chronic kidney disease and certain forms of cancer [1, 2]. Detection of the target receptor for Epo (EpoR) in cells other than erythroid progenitors, such as polymorphonuclear leukocytes, megakaryocytes, endothelial, myocardial and neural cells [3][4][5][6][7], suggests that Epo has other biological functions beyond erythropoiesis, and may have further potential therapeutic applications. These effects include improvement in congestive heart failure [8,9] and neuroprotection [10][11][12][13][14][15][16][17].* These authors contributed equally to this study. The idea that rHuEpo may have an important effect on the immune system, including both cellular and humoral type responses, derives from several lines of data, as recently reviewed [18]. For instance, clinical observations revealed that treatment with rHuEpo was associated with enhanced antibody production in hemodialysis patients, demonstrated for T cell-dependent antigens, such as tetanus toxoid and hepatitis B [19][20][21][22] as well as for the T cell-independent pneumococcal polysaccharide antigen [20]. Others have demonstrated enhancement of basal and mitogen-stimulated immunoglobulin production by cultured peripheral mononuclear cells (MNC) of dialysis patients treated ...

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…We centered on DCs as potential candidates that mediate the effects of EPO on lymphocytes, shown in the enhancement of both the cellular and humoral components of the immune system (Katz et al, 2007;Mittelman et al, 2001). Notably, DCs are the most potent APCs and are therefore capable of diverting the entire immune response according to the stimulatory signals that they receive (Katz et al, 2007;Mittelman et al, 2001).…”

“…Notably, DCs are the most potent APCs and are therefore capable of diverting the entire immune response according to the stimulatory signals that they receive (Katz et al, 2007;Mittelman et al, 2001). …”

“…The transgenic mouse over-expressing EPO (tg6) has been previously described (Heinicke et al, 2006;Katz et al, 2007;Ruschitzka et al, 2000). Female tg6 mice and their wt littermates were used at the age of 3-5 months.…”

“…Tyrophostin AG-490 (Sigma) was reconstituted in DMSO at 0.1 M and kept in the dark at -20°C. rHuEPO injections -C57BL/6 mice were injected subcutaneously three times every other day during a week, with 180 U rHuEPO or with diluent (negative control) as described (Katz et al, 2007).…”

“…More recently we noted EPO effects also on the humoral immune response of antigen-injected mice in both EPO-treated mice and tg6 mice (Ruschitzka et al, 2000;Vogel et al, 2003) -transgenic mice over-expressing human EPO (HuEPO) (Katz et al, 2007). Whereas these findings strongly suggest that EPO is an immunomodulator, the cellular mediators and underlying mechanisms are not understood, especially since EPO-Rs were not detected on lymphocytes ((Prutchi-Sagiv et al, 2006) and unpublished data).…”