The link between major histocompatibility complex antibodies and cell proliferation

Abstract

Experimental evidence indicates that donor specific antibodies targeting MHC class I and class II molecules can elicit the key features of transplant vasculopathy by acting on the graft vasculature in three ways: directly activating proliferative, pro-survival, and migratory signaling in the target endothelial and smooth muscle cells; increasing expression of mitogenic factors in vascular endothelial cells, creating a potential proliferative autocrine loop; and promoting recruitment of inflammatory cells, which produce mitogenic factors and elicit chronic inflammation, proliferation, and fibrosis. Here we review the experimental literature showing the complement and Fc-independent effects of MHC class I and II antibodies on graft vascular cells which may directly contribute to the proliferative aspect of transplant vasculopathy.

New insights regarding chronic antibody-mediated rejection and its progression to transplant glomerulopathy

“…Further supporting this concept, direct endothelial cell activation by DSA, especially human leukocyte antigen (HLA) class I, has elicited features of transplant glomerulopathy in experimental models [22]. Activated endothelial cells induce cell-signaling pathways promoting cell growth and survival.…”

Anti-HLA antibodies in regenerative medicine stem cell therapy

“…Several lines of evidence indicate that anti-HLA I and II antibodies on graft vascular cells contribute to the proliferative aspect of transplant or graft vasculopathy, a progressive vascular disease that develop in chronically rejected vascularized allografts [20].…”

“…Therefore, and based on organ transplantation [20], HLA-mediated signaling after ligation of HLA I and/or II on administrated allogenic SC with alloantibodies is conceivable, and might contribute to the regulation of SC implant fate. The query again is how these anti-HLA antibodies could operate in the course of SC therapy.…”

“…This is supported by the capacity of HLA signaling to, 1. activate two major cell survival pathways MAPK/Erk and PI3-kinase/Akt in different types of cells, promoting their survival, proliferation and in some instances differentiation [20,21,59], 2. upregulate various anti-apoptotic proteins among which Bcl-2 family of protein, which are known to protect from cell death during stress including oxidative stress that is common in injured myocardium [20].…”

“…Besides these ''classical'' mechanisms, evidence also exists into the relevance of antibody-induced HLA signaling in transplantation [20]. Indeed, while HLA molecules are principally viewed as antigen presenting structures, allowing a peptide to be recognized by the TCR in the genetic context of self-MHC, evidence that HLA/MHC molecules are also bona fide signal transduction receptors is now well documented [21].…”