Interleukin 10‐induced thrombocytopenia in normal healthy adult volunteers: evidence for decreased platelet production

Abstract

Recombinant human interleukin 10 (rhuIL‐10) inhibits the production of proinflammatory cytokines and has shown promise in the treatment of inflammatory bowel disease. Clinical trials have been accompanied by a reversible decline in platelet counts. We conducted a randomized, double‐blinded, placebo‐controlled, parallel group trial in 12 healthy volunteers to investigate the aetiology of rhuIL‐10‐induced thrombocytopenia. Eight volunteers received 8 μg/kg/d of rhuIL‐10 subcutaneously, while four subjects received a placebo alone for 10 d. A reversible decline in the platelet counts from a mean of 275 × 109/l to 164 × 109/l was observed in the IL‐10‐treated cohort (P = 0·012). A fall in the haemoglobin mean levels was also observed in the IL‐10‐treated cohort from 13·7 to 11·7 g/dl (P = 0·011). No significant change was observed in the bone marrow cellularity or myeloid/erythroid ratio or in the number of megakaryocytes per high‐powered field (HPF). A fall was observed in the number of megakaryocyte colony‐forming units (CFU‐MKs) after the administration of IL‐10 compared with those receiving the placebo (P = 0·068). No difference in the change in granulocyte–macrophage CFUs (CFU‐GMs), mixed lineage CFUs (CFU‐GEMMs) or erythroid burst‐forming units (BFU‐Es) was observed when comparing the IL‐10‐ vs. placebo‐treated groups (P > 0·465). Serum cytokine levels of thrombopoietin (TPO), IL‐6 and granulocyte–macrophage colony stimulating factor (GM‐CSF) were not decreased following IL‐10 administration. In fact, both TPO and GM‐CSF appeared to be slightly increased in the serum. All subjects underwent In111‐labelled platelet survival studies with liver/spleen scans to assess splenic sequestration prior to and then on day 7 of treatment. A significant reduction in splenic sequestration of platelets (P = 0·012) was observed in the IL‐10‐treated group, but not in the placebo‐treated subjects.

The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr−/−-dependent allergy mouse model

“…The granulocyte-macrophage colony-stimulating factor, which was reduced (see Figure 3), and other thrombopoietic factors such as IL-3 could fall within this category. In fact, this IL-10-associated thrombocytopenia has been reported recently by Sosman et al, 64 in human patients receiving a recombinant human IL-10 protein subcutaneously for 10 days. This study also unmasked a twofold reduction in the platelet counts in patients receiving the IL-10 protein when compared to the placebo cohort; it was also noted that the thrombocytopenia resolved once the patients stopped receiving protein with no observable lasting toxic effects.…”

Serum cytokine profiles of children with human enterovirus 71‐associated hand, foot, and mouth disease

“…In the current study, all four cases of death were due to respiratory dysfunction and severe pulmonary edema was reported in over a quarter of patients with severe HFMD, which may be linked to elevated IL‐10 and IL‐13 levels. IL‐10 has been reported in induce thrombocytopenia [Sosman et al, ], potentially causing platelet aggregation and increased pulmonary vascular permeability that contribute to respiratory dysfunction and failure [Mulligan et al, ]. Similarly, IL‐13 may induce pathophysiological features of asthma [Wills‐Karp et al, ], as observed in other viral pulmonary infections that include infection by respiratory syncytial virus (RSV), adenovirus, and influenza A [Anderson et al, ].…”

Interleukin‐10 in viral diseases and cancer: exiting the labyrinth?

“…Overall, IL‐10 was well tolerated at the administered doses. The most prominent hematological changes following subcutaneous or intravenous administration to healthy volunteers were a reduction in lymphocyte counts, an increase in neutrophil and monocyte counts (154–156), as well as thrombocytopenia resulting from decreased platelet production (157). In accordance with the anti‐inflammatory properties of IL‐10, the production of TNF and IL‐1β by whole blood in response to LPS and the expression of human leukocyte antigen (HLA)‐DR by monocytes was decreased (154–156).…”