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The in vivo intrasplenic cloning of haemopoietic cells was used as an experimental system for the study of some aspects concerned with the regulation of erythropoiesis. Experiments on the effects of polycythemia on the formation of erythroid clones demonstrated that the "feedback" suppression of such clones was inhibited if the polycythemic animals were kept under hypoxic conditions. Overloading with oxygen is, thus, an essential factor in the polycythemia-induced suppression of erythroid clones. Polycythemic animals which were transferred to hypoxic conditions for only 48 hours before the termination of the experiment showed the formation of erythroid clones. Analysis of clone formation following such short exposures to hypoxia suggests that the endogenous erythropoietin which had been functioning in this situation acted not upon the single clone-forming cell, but rather on small cell populations which derived from the clone-forming cells in the absence of erythropoietin. There is, therefore, an early, erythropoietin-independent phase of replication of the clone-forming cells. The application of erythopoietin only during this "early" phase of replication resulted in the formation of erythroid clones, which, following the discontinuation of erythropoietin, disappeared from the spleen. Similar results were obtained when the action of endogenous erythropoietin was terminated by subjecting animals to polycythemic conditions a few days after the injection of bone marrow. It appears that in both these cases the reduction in the number of spleen colonies following discontinuation of erythropoietin activity is due to the total maturation of the erythroid colonies, ending in the evacuation from the spleen of the mature red blood cells. The differentiation of the cloned cells is, thus, causally related to the cessation of the replicating effect of erythropoietin.

Polycythemic x-irradiated female mice, injected with 12-day fetal liver cells, showed 81% suppression of erythroid spleen colonies as compared with nonpolycythemic recipients. On the other hand, in male recipients only 16% suppression was observed. Hence, androgenic hormones seem to play a role in regulating erythropoiesis of explanted fetal stem cells. To test this, we examined the effect of testosterone injected into polycythemic female recipients on the production of erythroid colonies from fetal liver cells. Testosterone was found to alleviate the suppressive effect of polycythemia. Antierythropoietin prevented the appearance of erythroid colonies in testosterone-treated animals. Thus, testosterone seems to act by increasing the levels of, or susceptibility to erythropoietin. Under similar conditions, testosterone did not trigger the formation of erythroid colonies from bone marrow cells in polycythemic recipients. Hence, fetal cells can be induced to form erythroid colonies by doses of erythropoietin that are too low to induce erythroid colonies in bone marrow cells.

Castleman disease (CD) describes multiple distinct and heterogeneous disorders defined by common lymph node histopathology, including atrophic or hyperplastic germinal centers, prominent follicular dendritic cells, hypervascularization, polyclonal lymphoproliferation, and/or polytypic plasmacytosis. Unicentric CD (UCD) involves a solitary lymph node station that displays CD histopathology, whereas multicentric CD (MCD) involves multiple regions of enlarged nodes. Most UCD patients do not experience systemic symptoms and are successfully treated by removal of the enlarged node. In contrast, MCD involves constitutional symptoms, cytopenia, hepatosplenomegaly, fluid accumulation, cytokine storm-associated multiple organ system dysfunction, and is often fatal. In 1994, Kaposi sarcoma-associated herpesvirus/human herpesvirus-8 (HHV-8) was identified as the etiological driver of MCD in immunocompromised individuals. However, approximately 50% of MCD patients are HHV-8 negative (idiopathic MCD (iMCD)). Its idiopathic nature limits targeted treatment for iMCD patients who do not respond to anti-Interleukin-6 therapy. iMCD is itself heterogeneous, and recent work has identified at least one distinct sub-population of iMCD patients with a severe clinical presentation featuring thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO). Several hypotheses have been proposed to explain the pathophysiology of iMCD and UCD, all of which remain untested. One notable hypothesis entertains that iMCD and UCD are in fact driven by viral infection–either HHV-8 that is not detected by current diagnostic methods, a novel virus, or a known but unanticipated virus. In support of the last possibility, there are several case reports of associations with Epstein-Barr virus (EBV), HHV-6 and Hepatitis B virus (HBV); however, neither a systematic study of known viruses, nor a search for novel viruses in CD has been reported.