T-Cell Abnormalities in Patients with Myelodysplastic Syndromes: Improved Immunological Functions in Patients Treated with Recombinant Erythropoietin.
Authors: Prutchi-Sagiv Sara , Golishevski Nataliya , Katz Odelia , Oster Howard S. , Naparstek Elizabeth , Hoffman Michael , Neumann Drorit , Mittelman Moshe 
Published: October 2019

Erythropoietin (Epo) is being used to treat anemias. We have observed prolonged survival in patients with multiple myeloma (MM) on recombinant Epo (rHuEpo) (Mittelman, EJH 2004). Studies on mice suggested an Epo anti-MM immune effect (Mittelman, PNAS 2001; Katz, Acta Haem 2005), and we have also found improved immunity in rHuEpo-treated MM patients. Here we tested the effect of Epo on immune function in myelodysplastic syndrome (MDS). We tested 27 MDS patients (15 controls). We show immune defects in early (IPSS low/int1) MDS, that are more pronounced in progressive disease. Consistent with previous reports, and extending our analysis to other immunologic functions, we show that MDS patients have decreased lymphocyte counts, manifested mainly in reduced CD4+ T-cell percentage and reduced mononuclear cell (MNC) proliferation induced by phytohemagglutinin (PHA). In MDS, the basal function of both CD4+ and CD8+ T cells expressing the early activation marker CD69 was higher than in controls, but following PHA stimulation, the increment of these CD69+ cells was attenuated. MDS patients also had a decreased percentage of the CD4+ cells expressing the IL-2 receptor, CD25. Finally, in MDS the proportion of CD8+ T-cells expressing the co-stimulatory molecule CD28 was reduced. To test whether rHuEpo treatment had any effect on these parameters, we compared these functions in 14 MDS patients (early disease) on rHuEpo with 8 early MDS patients who were not on rHuEpo. The rHuEpo-treated group included 12 patients responding to rHuEpo (increased Hb; Epo-responders) and 3 patients who continued to require transfusions (Epo-non-responders). The results show a significant increase in PHA-mediated activation of both CD4+ and CD8+ T cells, and a tendency towards normalized CD4+ percentage. The non-responders also showed a tendency towards normalized T-cell percentage and number, but they did not show any augmented activation, or proliferation potential (Table, mean ± SE).

Our findings:

add to the other reports, regarding the immune dysfunction in MDS; show that MDS patients on rHuEpo for anemia, also benefit from improved immune function.

Taken together, our study suggests a potential role for rHuEpo as an immunomodulatory agent in MDS treatment.

Parameter Healthy Controls Non-Treated MDS Patients rHuEpo-treated MDS Patients Early MDS Late MDS Responders Non-Responders a. p<0.05 early MDS compared to healthy controls. b. P<0.05 advanced MDS compared to healthy controls. c. p<0.05 rHuEpo-treated early MDS compared to non-treated early MDS. Number of patients N = 15 N = 8 N = 4 N = 12 N = 3 CD4+ T cell (%) 47.3±1.9 36.4±5.4a 31.9±6b 42.9±4 44.7±8.7 CD8+ (%) 22.2±1.6 21.6±3.1 14.4±3.9b 23.4±3.7 21.7±2.8 CD4:CD8 2.4±0.3 2.2±0.7 3.0±1.3 1.9±0.2 2±0.2 PHA act-CD4+ (%) 57.1±3.9 33.6±5.4a 39.5±9.1 58.6±8.8c 36.7±14 PHA act-CD8+ (%) 60±4.5 40.3±8.7a 53.4±8.5 65.5±8.2c 23.7±2.8 Proliferation (%) 232.5±10 189±23 100±0 185±23 164.9±0 CD8+CD28+ (%) 73.2±5.4 34±8.1a 31±0.7b 41±7.8 34±0 CD4+CTLA-4+ (%) 3.5±0.3 6.3±0.9 24±0.6 11.6±1.2 NA CD8+CTLA-4+ (%) 2.4±0.7 2.8±0.5a 12±0b 4.8±1.9 NA CD4+CD25+ (%) 72.7±0 55.1±5a 41±6.9b 61±8.5 38±0