Chronobiology in hematology and immunology

Abstract

The hematopoietic and the immune systems in all their components are characterized by a multifrequency time structure with prominent rhythms in cell proliferation and cell function in the circadian, infradian, and circannual frequency ranges. The circulating formed elements in the peripheral blood show highly reproducible circadian rhythms. The timing and the extent of these rhythms were established in a clinically healthy human population and are shown as chronograms, cosinor summaries and, for some high‐amplitude rhythms, as time‐qualified reference ranges (chronodesms). Not only the number but also the reactivity of circulating blood cells varies predictably as a function of time as shown for the circadian rhythm in responsiveness of human and murine lymphocytes in vitro to lectin mitogens (phytohemagglutinin and pokeweed mitogen). Some circadian rhythms of hematologic functions appear to be innate and are presumably genetically determined but are modulated and adjusted in their timing by environmental factors, so‐called synchronizers. Phase alterations in the circadian rhythms of hematologic parameters of human subjects and of mice by manipulation of the activity‐rest or light‐dark schedule and/or of the time of food uptake are presented. Characteristically these functions do not change their timing immediately after a shift in synchronizer phase but adapt over several and in some instances over many transient cycles. The circadian rhythm of cell proliferation in the mammalian bone marrow and lymphoid system as shown in mice in vivo and in vitro may lend itself to timed treatment with cell‐cycle‐specific and nonspecific agents in an attempt to maximize the desired and to minimize the undesired treatment effects upon the marrow. Differences in response, and susceptibility of cells and tissues at different stages of their circadian and circaseptan (about 7‐day) rhythms and presumably of cyclic variations in other frequencies are expected to lead to the development of a chronopharmacology of the hematopoietic and immune system. Infradian rhythms of several frequencies have been described for numerous hematologic and immune functions. Some of these, i.e., in the circaseptan frequency range, seem to be of importance for humoral and for cell mediated immune functions including allograft rejection. Infradian rhythms with periods of 19 to 22 days seem to occur in some hematologic functions and are very prominent in cyclic neutropenia and (with shorter periods) in its animal model, the grey collie syndrome. Low‐frequency rhythms in cell production and in the number of circulating leukemic cells have been found in some patients with chronic myelogenous leukemia. Circannual variations of several hematologic parameters have been described. Among those are cell proliferation of granulocytic bone marrow in soft agar cultures (CFU‐C) in mice and circannual variations in lymphocyte subtypes and functions. Chronobiologic considerations are essential in the design of animal experiments and human studies. High‐amplitude rhythms of a number of parameters may have diagnostic implications and should be evaluated against time‐qualified reference ranges. Low‐amplitude rhythms may not be of diagnostic importance at this time but do indicate functional changes in the cell systems studied and may be related to changes in susceptibility and responsiveness to a wide variety of stimuli. Quantitative rhythm parameters obtained by statistical methods of rhythmometry lend themselves as new endpoints in the study of the hematopoietic and immune systems. The multifrequency time structure of the mammalian organism is an essential part of its function and, as a morphology in time, complements its anatomy in space and in many aspects may be instrumental in maintaining the integrity of the latter.