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Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3222-3229
By
From the Institute for Medical Informatics, Statistics and
Epidemiology, University of Leipzig, Leipzig, Germany; the Division of
Hematology/Oncology, University of Kentucky Medical Center, Lexington,
KY; and the Groningen Institute for Drug Studies, University of
Groningen, Groningen, The Netherlands.
We investigated how in vivo effects of single hematopoietic
cytokines change if given in combination for a prolonged time. Mice
were treated with every combination of recombinant human (rh)
erythropoietin (EPO), rh granulocyte colony-stimulating factor (G-CSF),
recombinant rat (rr) stem cell factor (SCF), and rh interleukin (IL)-11 by continuous infusion over 7 days (full factorial
design with three dose levels for each cytokine). Burst-forming
unit-erythroid (BFU-E), colony-forming unit-erythroid (CFU-E), and
colony-forming unit-granulocyte-macrophage (CFU-GM) were determined in
bone marrow and spleen, reticulocytes, hematocrit, granulocytes, and
thrombocytes in the peripheral blood. An analysis of variance (ANOVA)
and multiple comparison of means was used to evaluate the data. For
several cell types, cytokine effects superimposed in an additive way if combined. However, in a large number of circumstances, nonadditive pairwise interactions were found. They differed in type and magnitude involving high-dose saturation, high-dose antagonistic effects, and
even effect reversals (qualitative interactions). Hence, in general, it
was not possible to foresee the combination effects on the basis of
existing knowledge of single effects. On the other hand, the cytokine
network was robust and no system hazards were observed under multiple
cytokine combinations. The results illustrate that the cytokine network
has nonlinear dynamic properties in vivo with dose-response
characteristics of one cytokine being continuously modified by other
cytokines.
THE IN VIVO EFFECTS of exogenous
administration of single cytokines, among them erythropoietin (EPO),
granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF),
and interleukin (IL)-11, have been extensively described. EPO is well
known as a specific stimulator of erythroid cell production in
vivo.1 G-CSF likewise stimulates granulopoiesis with
certain side effects on erythropoiesis and the hematopoietic stem cells
most likely caused by induction of migration of stem and early
progenitor cells from bone marrow to the spleen.2-6 SCF is
assumed to have a stimulatory effect on the stem cell compartment and
therefore its exogenous application leads to a general stimulation of
hematopoiesis.7-10 The same holds true for IL-11, which in
addition seems to induce strong migration of stem and early progenitor
cells from the bone marrow to the spleen in mice.11,12
Hematopoietic growth factors have redundant properties, ie, different
factors can lead to the same effect. In addition, they are pleiotropic,
meaning that one cytokine is able to mediate different
effects.13 For a detailed understanding of the quantitative
features of the cytokine network in vivo, it is however important to
understand how much and in which way single cytokine effects are
modified by other cytokines and how far this is
concentration-dependent.
It is the objective of this study to investigate in greater detail how
growth factor effects are modified by each other if given
simultaneously in vivo for a prolonged time. Simple effect superpositioning and also various kinds of synergistic or inhibitory interactions could result. To address these questions, we previously analyzed the in vivo effects of combined administration of only two
growth factors such as G-CSF and EPO,14 EPO and
SCF,10 EPO and IL-11.12 Other investigators
have undertaken similar experiments.8,15-18
Here we report about the in vivo effects of a combined simultaneous
administration, investigating all possible combinations of EPO, G-CSF,
SCF, and IL-11. We used a full-factorial experimental design with three
dose levels of each cytokine (placebo, medium, and high dose). This
design therefore involved 34 = 81 different dose
combinations. Two mice were examined at each design point. This design
enabled us to detect single cytokine effects, as well as second, third,
or fourth order cytokine interactions. Statistically, a second order
interaction exists if the relative effects of one cytokine over its
dose range depend on the level of one other cytokine. A third order
interaction exists if these pairwise effects again depend on the levels
of a third cytokine etc. We used an analysis of variance (ANOVA) and
multiple mean comparisons (Scheffé-test) as appropriate
statistical methods to evaluate the (interaction) effects.
The objective of our investigation was explorative in two respects.
First, we wanted to obtain an insight into the complex interaction
structure of the cytokine network in vivo, and second we wanted to see
whether a factorial study approach would be an informative strategy.
Mice
Hematopoietic Growth Factors
Administration of Growth Factors Growth factors were appropriately diluted, mixed, and administered by subcutaneously implanted osmotic mini pumps (type Alzet 1007D or 2002, Alza Corp, Palo Alto, CA). Delivery rates of these mini pumps were reported by the company to be constant over a 2-week period. This was confirmed by some pilot studies that we performed (unpublished data). To test whether the implantation of these pumps by itself affected hematologic values, we assessed the effect of a 7-day and 14-day implantation of pumps filled with saline. No changes compared with normal, untreated mice were observed (data not shown). To cover a whole dose response range for each single cytokine, we chose dose levels that were expected to give a medium and a high response. Mice were treated with 0, 20, or 80 µg/kg/d rhIL-11, with 0, 40, or 100 µg/kg/d rrSCF, with 0, 10, or 100 µg/kg/d rhG-CSF, and with 0, 2.5, or 25 U/d rhEPO, further to be called levels 0 (none), 1 (medium), and 2 (high) for each cytokine, respectively. Cytokines were administered for 7 days in all possible dose combinations. Hematologic parameters were evaluated at day 7 of treatment.Progenitor Cell Assays and Calculation of Total Body Cell Numbers Femur and spleen single cell suspensions were made according to standard procedures. BFU-E, CFU-E, and CFU-GM were cultured with the methylcellulose method of Iscove and Sieber.19 In addition, BFU-E and CFU-GM were stimulated with 100 ng/mL rrSCF, 10 ng/mL recombinant mouse (rm) GM-CSF (supplied by Behringwerke, Marburg, Germany) and 2 U/mL rhEPO. CFU-E were stimulated with 500 mU/mL rhEPO. These culturing conditions resulted in optimal colony growth. Total bone marrow cell numbers were calculated under the assumption that one femur contains 6% of total marrow.20 Total body cell numbers were calculated as follows: Total = Femur × 17 + spleen. Circulating cells in the blood were ignored.Blood Values Blood was obtained from the orbital plexus before the mice were killed. Hematocrit percentages, reticulocytes percentages, granulocytes (106/mL), and platelets (106/mL) were determined according to standard procedures.Statistical Methods ANOVA was used to detect significant main effects of single cytokines and interactions of cytokine combinations. All effect estimates are statistically independent of each other due to the underlying additive model of the ANOVA. We used a full factorial design with two measurements at each design point (34 × 2 = 162 mice). Due to the hidden replications in this factorial study design, highly efficient effect estimates were expected.21 However, an ANOVA is neither able to interpolate dose-response relationships nor detect the direction of effects. Cytokine doses are coded as ordered categories (dose levels 0, 1, and 2). To show significant differences of individual means, we performed multiple post hoc comparisons of means using the Scheffé-test. All hematologic parameters except hematocrit, reticulocytes, and thrombocytes were log-transformed to achieve homogeneity of variance and normal distribution. Our findings are visualized as three-dimensional bar diagrams showing mean cell counts (Z-axis) according to the dose levels of two cytokines (X- and Y-axis). It has to be emphasized that these mean cell counts are averaged over all possible levels of all other cytokines, generally involving 18 mice.
Table 1 summarizes the essential results of the ANOVA. Significance levels of all effects with P < .01 can be read from the table. The effect direction of significant main effects (all of them have monotonic characteristics) is given by the small arrows. Such effect directions make no sense for interaction effects.
EPO Erythropoiesis. EPO increased all erythroid cell stages except the BFU-E in the bone marrow. In the reticulocyte compartment, this stimulatory effect is lessened and in the splenic CFU-E compartment, it is strengthened by G-CSF. These effects are real interactions (deviating from additivity on the log-transformed scale). For the reticulocytes, inhibition is only seen at high EPO levels (Fig 1A) and in the splenic CFU-E, we have a saturation effect at high levels of both cytokines (Fig 1B). In contrast, there are additive effects without interactions in the bone marrow CFU-E (stimulation by EPO, inhibition by G-CSF; Fig 1C). IL-11 shows an additive stimulatory effect on the reticulocytes, which leads to a maximum response for the combination high EPO and high IL-11 (Fig 1D). A similar additive pattern is seen in the splenic erythropoietic precursors (data not shown). The EPO-stimulation on the hematocrit is slightly reduced by IL-11 (Fig 1E), while IL-11 does not influence the stimulation caused by EPO in the bone marrow.
Granulopoiesis. Regarding granulocytes, we found a slight stimulating effect of EPO (data not shown). Also the splenic CFU-GM were stimulated by EPO (Fig 1F and G). Both effects showed additive superpositioning with the G-CSF and IL-11 effects suggesting mutual independence of the regulatoric mechanisms. Thrombopoiesis. Averaged over all other cytokine levels, no EPO effect on platelets was detectable. But, if looking at the interaction of EPO and G-CSF, we found that EPO, if given at high dose, modulates the G-CSF inhibition (Fig 1H). G-CSF Erythropoiesis. G-CSF decreased the reticulocyte numbers, as well as the erythroid progenitors in the bone marrow (Figs 1A, 2B and D). However, the hematocrit remained unchanged under G-CSF at day 7 (data not shown). Splenic erythroid progenitors were slightly stimulated (Figs 1B, 2A and C). Interactions of G-CSF with EPO have already been discussed above. No interaction effect was detected between G-CSF and IL-11. There were statistically significant interactions between G-CSF and SCF in the BFU-E. In the spleen, we noted that the stimulation by SCF disappears at high G-CSF level (Fig 2A), whereas a depressive effect of SCF in the bone marrow BFU-E was only seen under additional G-CSF application (Fig 2B). In the splenic CFU-E, we found an additive superpositioning of both stimulatory effects, G-CSF and SCF (Fig 2C), whereas for the bone marrow CFU-E, the high-dose inhibition of G-CSF was weakened somewhat by high-dose SCF (Fig 2D).
Granulopoiesis. Blood granulocyte counts were increased by G-CSF (Fig 2E and H). The same holds true for splenic CFU-GM (Fig 2F and I), whereas bone marrow CFU-GM numbers were decreased (Fig 2G and J). Simultaneous effects of G-CSF with IL-11 in the granulocyte compartments were shown to be of an additive kind (Fig 2E). The same holds for G-CSF and EPO on splenic CFU-GM (see above, Fig 1F). IL-11 and G-CSF showed interaction effects in the CFU-GM: in the spleen there was a superpositioning effect with saturation at high-dose levels (Fig 2F) and in the bone marrow, we could see lower suppression with a combination of high G-CSF and medium IL-11 compared with no or high IL-11 (Fig 2G). The G-CSF × SCF interaction turns out to show saturation characteristics in the granulocytes and the splenic CFU-GM (Fig 2H and I). In the bone marrow CFU-GM, a decreasing effect of G-CSF is only seen under simultaneous SCF administration (Fig 2J). Thrombopoiesis. Platelets were suppressed under G-CSF. This is modulated by EPO (as mentioned above, Fig 1H) and by IL-11 (data not shown). The latter effect is simply additive. A qualitative interaction was found for SCF and G-CSF with stimulation at moderate doses of each cytokine alone and depression when given jointly (Fig 2K). IL-11 Erythropoiesis. IL-11 stimulated reticulocytes and splenic progenitors (Fig 3A and B). This effect was not seen in the bone marrow. However, the hematocrit was reduced by IL-11 (Fig 1E). Interactions of IL-11 with EPO and G-CSF have been reported above. An interesting interaction was seen between IL-11 and SCF in the splenic CFU-E. There was an extreme gain if IL-11 and SCF were administered simultaneously at medium or high and high doses, respectively (Fig 3B). Although this interaction effect has been shown to be statistically significantly different at different G-CSF levels, these differences were not of a qualitative kind. The above mentioned gain was independent of the G-CSF level. G-CSF seems to induce only a slight quantitative change of the described IL-11 × SCF interaction effect (data not shown). This IL-11 × SCF interaction effect is not detectable in the bone marrow and likewise not in the reticulocytes (Fig 3A) at this time point.
Granulopoiesis. Granulocytes are also slightly stimulated by IL-11 (Fig 3C). IL-11 reduces the CFU-GM numbers in the bone marrow slightly (Fig 2G), but increases them in the spleen (Fig 3D). Important simultaneous effects of IL-11 on granulopoiesis are detectable with G-CSF (reported above) and SCF. For granulocytes, IL-11 and SCF act as additive stimulators (Fig 3C). The same holds for splenic CFU-GM (Fig 3D). Thrombopoiesis. A weak stimulation of the platelets is detectable under IL-11, which is reduced under high SCF (Fig 3E). This interaction effect turns out to be not statistically significant. Likewise, no significant interaction with other cytokines is seen for these cells. SCF Erythropoiesis. Effects are only seen in the splenic progenitor compartments (Figs 2C and 3B) where the cytokine acts in a stimulating way. Granulopoiesis/thrombopoiesis. Granulocyte numbers, as well as splenic CFU-GM, are elevated by SCF (Fig 3C and D), whereas thrombocytes are reduced (Fig 3E). Interactions with the other cytokines have already been reported.
As others have previously shown, we notice that each of the cytokines applied has specific dose-dependent hematopoietic effects. However, many of these effects are modified in the presence of other cytokines in such a way that the effect characteristics are changed in a quantitative or even qualitative way. Main effects. EPO showed the well-expected stimulatory effects on erythropoiesis. Furthermore a weak, but significant, stimulatory effect on splenic CFU-GM and granulocyte numbers was found. We interpret this result as a consequence of an EPO-induced cell migration from the marrow to the spleen where both the erythropoietic and granulopoietic lineage find an increased amplification.22 Interactions. Under the assumption that two different cytokines act completely independent of each other, one expects that the shape of the dose-response characteristics of one cytokine is not changed, but only shifted up or downwards depending on the level of the second cytokine. Deviations from this parallel shift situation are called interactions. An interaction is called qualitative if it reverses the sign of the differences between the mean values. Interactions without a change of the effect direction are called quantitative. Third or fourth order interactions imply analogous dependencies of three or four cytokines.
Submitted August 4, 1997;
accepted December 18, 1997.
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© 1998 by The American Society of Hematology.
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| Copyright © 1998 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Abstract
Introduction
Abstract
e 27, 04103 Leipzig, Germany.
a possible pathomechanism of human cyclic neutropenia.
Cell Prolif
27:655,
1994