Immunological aspects of hibernation as leads in the prevention of acute organ injury

PhD ceremony: Mr. H.R. Bouma, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Immunological aspects of hibernation as leads in the prevention of acute organ injury

Promotor(s): prof. R.H. Henning, prof. F.G.M. Kroese

Faculty: Medical Sciences

Mammalian hibernation consists of periods of low body temperature (~4°C; “torpor”), interspersed by euthermic periods, without signs of organ injury. We explored the modulation of the immune system during natural and pharmacological induced torpor, with the ultimate aim to exploit such mechanisms to limit organ injury in the clinical setting. In a retrospective study of patients that underwent cardiac surgery employing cardiopulmonary bypass (CPB), and an animal model of CPB, we revealed hypothermia and inflammation as important players in the etiology of renal injury following CPB. Therefore, we studied which mechanisms might underlie the protection of organ injury during hibernation. One such a mechanism might be the reversible clearance of circulating leukocytes during torpor. Neutropenia during torpor is probably due to margination of neutrophils induced by low temperature, while lymphopenia is secondary to reduced egress of lymphocytes from secondary lymphoid organs due to a decreased plasma level of Sphingosine-1-phosphate. Although the number of lymphocytes restores upon arousal, the function of the immune system remains suppressed, leading to a reduced capacity to induce a humoral immune response during hibernation. To assess whether similar changes could be induced pharmacologically, we tested such a strategy using 5’-AMP in mice and demonstrated that 5’-AMP administration in mice leads to a reversible reduction in the body temperature and temperature-independent retention of lymphocytes. Pharmacologic induction of a torpor-like state with increased resistance to hypothermia and a reduced immune function may be of therapeutic use to improve outcome following CPB.