Leukocyte Integrin Mac-1 Promotes Acute Cardiac Allograft Rejection

Abstract

Background— In allograft rejection, recipient leukocytes and alloantibodies first target donor endothelial cells. Although the leukocyte integrin Mac-1 (α Mβ2 , CD11b/CD18) facilitates cell–cell interactions among leukocytes and interactions between leukocytes and endothelial cells or platelets, its role in allograft survival and vasculopathy is incompletely defined. Methods and Results— This study examined parenchymal rejection and graft arterial disease after total allomismatched cardiac transplantation (BALB/c donor heart and B6 recipients) in wild-type (WT) and Mac-1-deficient (Mac-1 −/− ) recipients. Recipient Mac-1 deficiency attenuated parenchymal rejection and significantly prolonged cardiac allograft survival from 8.3±1.3 days in WT recipient allografts (n=18) to 13.8±2.3 days in Mac-1 −/− recipient allografts (n=6; P <0.0001). Accumulation of neutrophils and macrophages significantly decreased in Mac-1 −/− compared with WT recipients. Adoptive transfer of WT but not Mac-1 −/− macrophages to Mac-1 −/− recipients exacerbated parenchymal rejection and reduced allograft survival; in contrast, adoptive transfer of WT neutrophils did not affect graft survival. Mac-1 −/− macrophages expressed significantly lower levels of costimulatory molecules both in vivo and in vitro, and mixed lymphocyte reaction using alloantigen-primed Mac-1 −/− macrophages resulted in significantly lower antigen-presenting function than for WT macrophages. Tumor necrosis factor-α production also fell in cultures with Mac-1 −/− macrophages. Despite attenuation of acute rejection, recipient Mac-1-deficiency did not prevent late graft arterial disease. Conclusions— These studies demonstrate critical participation of Mac-1 in alloresponses during cellular allograft rejection. These observations establish a molecular target for modulating recipient responses to prolong graft survival.

Identification of Activators of ERK5 Transcriptional Activity by High-Throughput Screening and the Role of Endothelial ERK5 in Vasoprotective Effects Induced by Statins and Antimalarial Agents

“…Occlusion (GAD) was scored on a scale of 0 to 4 on the extent of luminal occlusion averaged over 10 arteries (0, <10 %; 1, 10–25%; 2, 25–50%; 3, 50–75%; and 4, >75% occlusion of the vascular lumen) as described previously (27). …”

Effects of Immunosuppressive agents on neutrophils inflammatory response in humans: An inflammatory perspective on coronary allograft vasculopathy

“…Because neutrophils are able to release numerous mediators, including pro-inflammatory (IL-1α/β; -6; -7; -8; -9; -16), pro-inflammatory/angiogenic (tumor growth factor TGF-α; vascular endothelial growth factor VEGF), and anti-inflammatory mediators (IL-1 receptor antagonist (IL-1RA), TGF-β), they likely play a pivotal yet not well characterized role in the initiation and the development of CAV [28] . Previous studies have demonstrated the potential deleterious role of neutrophils during myocardial reperfusion immediately after CTx in rodents, notably via neutrophil activated αMβ2 integrin complexes (CD11b/CD18) [29,30] . These studies reported that β2 integrin mediated neutrophil infiltration and accumulation in the cardiac allograft tissue was associated with acute rejection in mice.…”

The Role of Chemokines in Transplant Graft Arterial Disease

“…For complete T cell activation, costimulatory molecules such as CD40, B7 molecules (CD80, CD86), OX40L, ICOS ligand, or PDL1 and PDL2 (programmed cell death ligand) must also ligate host T cell cognate receptors; ␤-integrins can also affect antigen presentation. 19 Recruited and activated T cells then secrete cytokines such as tumor necrosis factor (TNF)-␣ and IFN-␥ that amplify the immune response, increase EC adhesion molecule expression, and lead to further recruitment of macrophages and T lymphocytes. In turn, activated macrophages and lymphocytes express cytokines and growth factors such as plateletderived growth factor, fibroblast growth factor, and transforming growth factor (TGF)-beta (TGF-␤), that promote the recruitment and proliferation of smooth muscle-like cells in the intima and drive extracellular matrix synthesis.…”

“…57 MCP-1 also plays an important contributory role in the pathogenesis of acute organ rejection and GAD. 63 Interestingly, statins attenuate the production of these chemokines in ECs, SMCs, and monocytes, 19,64 and also reduce CCR2 and CCR5 expression by both ECs and macrophages, attenuating GAD. 65 …”

“…Macrophages can also function as a potent APCs. 19 The CC chemokines (eg, MCP-1/CCL2, MIP-1␣/CCL3, and RANTES/CCL5) are the dominant mediators in recruiting monocytes to rejecting organs. 61 Genetic deletion, antibody blockade, or inhibition of either MCP-1 or RANTES substantially reduces intragraft macrophage and T cell accumulation and attenuates allograft rejection.…”