High-Fat Diet–Induced Obesity Enhances Allograft Rejection

Abstract

Background Obesity promotes a state of low-grade inflammation that exacerbates chronic inflammatory diseases such as asthma and inflammatory bowel disease. In transplantation, the survival of organs transplanted into obese patients is reduced compared to allografts in lean recipients. However, whether this is due to increased alloimmunity remains to be addressed conclusively. Methods We used a mouse model of high fat diet (HFD)-induced obesity and assessed immune responses to allogeneic stimulation in vitro, allogeneic splenocyte immunization in vivo, and allogeneic heart transplantation. Results Our results indicate that HFD altered the composition and phenotype of splenic antigen-presenting cells (APCs) that led to their enhanced capacity to stimulate T cells. Immunization with allogeneic splenocytes in vivo resulted in increased alloreactivity, as determined by IFNγ production. Moreover, cardiac allograft rejection in HFD mice was modestly accelerated compared to aged-matched control animals fed a low fat diet (LFD), correlating with enhanced alloreactive T cell function. Conclusions Our results highlight the increased alloresponse triggered by HFD-induced obesity and its negative impact on transplant outcome.

Impact of environmental factors on alloimmunity and transplant fate

“…Thus, overall antigen presentation in hyperlipidemic mice remains unchanged or slightly impaired. These results differ from those of a recent study in which APCs were found to have greater stimulatory capacity if animals were fed an HFD for over 12 weeks, when obesity-induced inflammation is prominent (53). Also, in this study, control mice were fed a nutrient-matched low-fat diet, rather than normal chow, possibly revealing a lower stimulatory capacity of control APCs.…”

“…Thus, hyperlipidemia leads to accelerated rejection independently of obesity and hyperglycemia. Accelerated rejection of minor antigen-mismatched cardiac grafts was also observed in mice on an HFD compared with mice on a nutrient-matched low-fat diet (53). Together, these data point to a role for hyperlipidemia in transplant rejection.…”

Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4 + T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals

“…We found that rejection of HY-mismatched skin was significantly accelerated in HFD as compared to CD female recipients (Figure 1E) (Molinero et al., 2016). Activation of CD4 + T cells and their localization to the graft are known to be instrumental to rejection in this system (Chen et al., 2003).…”

Impact of hyperlipidemia on alloimmunity

“…Thus, rejection of heart grafts is accelerated independently of obesity, hyperglycemia, high fat diet and ApoE−/− mutation status, but is correlated with degree of hyperlipidemia. Accelerated rejection of cardiac grafts in mice on a high fat diet has recently been confirmed by a study performed comparing mice on a high fat diet with mice given a low fat diet (62). Together, these data point to a role for hyperlipidemia in transplant rejection.…”