Haptoglobin Enhances Cardiac Transplant Rejection

Abstract

Rationale Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated. Objective To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation. Methods and Results We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and up to 72 hours after transplantation revealed that 22 proteins including haptoglobin, a known anti-oxidant, are significantly upregulated in our grafts. Through the use of haptoglobin deficient mice, we show that 80% of haptoglobin deficient recipients treated with peri-operative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited > 100 days survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild type recipients rejected their transplants by 21 days post transplantation. We found that haptoglobin modifies the intra-allograft inflammatory milieu by enhancing levels of the inflammatory cytokine IL-6 and the chemokine MIP-2 but impair levels of the immunosuppressive cytokine IL-10. Haptoglobin also enhances dendritic cell graft recruitment and augments anti-donor T cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection. Conclusions Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported anti-oxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions.

Platelets contribute to the initiation of colitis‐associated cancer by promoting immunosuppression

“…In addition to SAA proteins, we found that circulating levels of haptoglobin, another APP that is overexpressed in platelet releasates from cancer mice, reached levels equal to 1 mg mL −1 , and remained elevated when tumor developed. It is noteworthy that, in addition to its antioxidant properties, haptoglobin can regulate the host immune response , with anti‐inflammatory and proinflammatory effects, depending on pathological context . Understanding the contribution of haptoglobin, and other identified APPs, to CAC will require further investigation.…”

Danger signals in regulating the immune response to solid organ transplantation

“…In vitro studies demonstrated that haptoglobin exerts its immune effects through increased expression of the proinflammatory cytokines IL-6 and macrophage inflammatory protein-2 (MIP-2), while reducing levels of the antiinflammatory cytokine IL-10. Haptoglobin also enhanced DC graft recruitment and augmented antidonor T cell responses (56). Previous studies using a murine skin transplant model demonstrated that haptoglo-…”

“…Haptoglobin is an acute-phase serum protein that, in addition to binding free hemoglobin, influences free radical formation and angiogenesis. More recently, haptoglobin has been described as a novel mediator of innate immune activation after heart transplantation (55,56). Haptoglobin expression is increased in the context of both human and experimental cardiac transplant rejection, and targeted depletion of haptoglobin led to sustained costimulatory blockade-induced tolerance in an experimental heart transplant model, suggesting that its presence impairs maintenance of tolerance.…”

Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart

“…Interestingly, acute phagocytosis and innate inflammation during allograft IRI has been linked to chronic pathophysiology. For example, perioperative and acute inflammation are prognostic for worse long-term transplant outcome ( 201 , 202 ). Graft reperfusion may trigger reperfusion-associated cell death ( 38 ) and cell necrosis occurs during allograft cold storage and continues in allograft reperfusion.…”