Erythropoietin treatment in advanced multiple myeloma is associated with improved immunological functions: could it be beneficial in early disease?

Abstract

SummaryErythropoietin (Epo) is the main growth regulator of red blood cells, and recombinant human erythropoietin (rHuEpo) is thus used in clinical practice for the treatment of anaemia, primarily in kidney disease and cancer. rHuEpo treatment was found to be associated with prolonged survival of multiple myeloma (MM) patients. This clinical observation was then supported by studies on murine myeloma models. It thus appeared that rHuEpo had an anti-myeloma effect, causally related to an immunomodulatory function of rHuEpo. The present study investigated whether rHuEpo-treated MM patients acquire improved immunological functions. Treatment with rHuEpo, prescribed for anaemia that occurs in advanced disease, was associated with effects on a variety of immunological parameters and functions. This was expressed in an actual normalisation of the CD4:CD8 cell ratio, enhanced T cell phytohaemagglutinin-mediated activation and proliferation potential, T cell expression of the costimulatory CD28 and inhibitory CTLA-4 molecules, as well as reduced interleukin-6 serum values to normal levels. Furthermore, it was demonstrated that immunological abnormalities manifest in patients even in the early stages of MM. Our findings thus suggest that rHuEpo treatment might be effective in the early stages of MM, before anaemia develops. It is expected that this would boost the immune system, consequently achieving an anti-myeloma function; affecting disease progression and improving the prognosis.

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

“…This phenomenon is one of the major defects of the immune system observed in MM patients. Another indicator for a possible role of EPO on DCs is the finding that, in addition to its anti-neoplastic effects in MM, EPO also has immunomodulatory effects that reduce immunosuppression in MM (Prutchi-Sagiv et al, 2006).…”

“…EPO treatment in MM patients was associated with effects on given immunological parameters and functions, including normalization of the CD4:CD8 cell ratio, as well as enhanced phytohemagglutinin-mediated T cell activation and proliferation (Prutchi-Sagiv et al, 2006).…”

“…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).…”

Activities of erythropoietin on tumors: An immunological perspective

“…The authors of the present study [7] could not previously detect EPOR in mouse spleen cells or in human lymphocytes by RT-PCR [11], while others described EPO binding on a B cell line [19]. Also in consideration of the lack of effect of EPO on T cell activation when whole blood cell cultures are stimulated with EPO, Katz et al [7] hypothesize that other cells, such as antigen presenting cells, might mediate the effects on B and T cells.…”

“…The effect of EPO on MM was also reproduced in murine models, where EPO promotes the development of an effective and long-lasting anti-tumor specific immune response mediated via activated CD8 + T cells [10]. By specifically investigating EPO effects on immunological functions in advanced MM patients, a study from the same group showed that EPO increased T cell activation and proliferation, normalized the CD4:CD8 T cell ratio, decreased the percentage of CD8 + T cells expressing the inhibitory molecule CTLA-4, and increased CD8 + T cells expressing the costimulatory CD28 [11].…”