Emerging from the confusion of the early days of hematopoietic cytokine discovery was a simple view that for each type of blood cell there would be a single lineage-specific regulator and for each cytokine there would be a specific and defined function. This has not turned out to be the case—blood cell lineages are affected by many different cytokines throughout their development. In addition, all cytokines have been found to have a diverse array of actions, some direct, others indirect, even for the most selective of agents, EPO and G-CSF. Other cytokines have very complex actions, especially as part of overlapping cytokine networks with hereto unforeseen interactions and interdependencies.

In general, most hematopoietic cytokines are short lived in the blood and require repeated frequent injections to clearly see their actions. To improve their utility as therapeutics, the exposure profile of some have been modified by relatively simple pegylation, for example, G-CSF [pegfilgrastim (76)] and EPO [PEG-EPOb (88)] and that of others by more complex glycoengineering, for example, EPO [darbepoetin alfa (104)]. Some have been mimicked by peptides, for example, EPO [hematide (89)], TPO (AMG 531), or even small molecules, for example, TPO [eltrombopag (98)], while others have been conjugated into chi-meric molecules, for example, G-CSF and Flt-3 ligand [progenipoietin (105)].

The field of hematopoietic cytokine biology continues to develop as complex pathways are deconvoluted, and surprises continue to emerge (27). For a number of these factors, end-cell regulation has emerged as a common method of homeostatic control of cellular pathways, with cytokines serving as the central humoral mediators. It remains to be seen how this will be exploited further for the development of cytokine therapeutics with utility in human medicine.

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