Very Late Antigen 1 Blockade Markedly Promotes Survival of Corneal Allografts

Abstract

To investigate the role of very late antigen 1 (VLA-1) (also known as integrin receptor ␣ 1 ␤ 1) in corneal transplantation inflammation and allograft survival. Methods: Cell infiltration and vasculogenesis (both angiogenesis and lymphangiogenesis) associated with allodisparate corneal transplantation were assessed in VLA-1-deficient conditions and controls by immunofluorescent microscopic studies. Corneal allograft survival was also assessed after anti-VLA-1 antibody treatment and in VLA-1 knockout recipient mice. Results: Anti-VLA-1 antibody treatment leads to a profound reduction in the granulocytic, monocytic, and T-cell infiltration after corneal transplantation. In addition, corneal angiogenesis and lymphangiogenesis were both significantly suppressed in VLA-1 knockout mice. Remarkably, universal graft survival was observed in both anti-VLA-1 antibody treatment and knockout mice. Conclusions: Very late antigen 1 blockade markedly reduces inflammation and inflammation-induced tissue responses, including vasculogenic responses, associated with corneal transplantation and promotes allograft survival. Clinical Relevance: These studies offer insights into important integrin-mediated mechanisms of corneal transplant-related inflammation and provide possible new integrin-based immunotherapies for transplant rejection.

Angiopoietin-2 Blockade Promotes Survival of Corneal Transplants

“…6 More recently, it was reported that anti-Ang-2 treatment reduced the number of macrophages in the corneas 10 days after suture placement. 10 Because macrophage infiltration peaks around 2 weeks after corneal transplanation, 11 we next evaluated the effect of Ang-2 blockade on corneal macrophages at 2 weeks after transplantation. As shown in Supplementary Figure S1, our results showed that Ang-2 blockade tended to reduce the number of macrophages inside the grafted corneas though the data were not statistically significant ( P = 0.9).…”

Angiopoietin-2 Blockade Promotes Survival of Corneal Transplants

“…6 More recently, it was reported that anti-Ang-2 treatment reduced the number of macrophages in the corneas 10 days after suture placement. 10 Because macrophage infiltration peaks around 2 weeks after corneal transplanation, 11 we next evaluated the effect of Ang-2 blockade on corneal macrophages at 2 weeks after transplantation. As shown in Supplementary Figure S1, our results showed that Ang-2 blockade tended to reduce the number of macrophages inside the grafted corneas though the data were not statistically significant ( P = 0.9).…”

Mechanoinduction of lymph vessel expansion

“…β1 Integrins link the ECM with the actin cytoskeleton, thus connecting the extracellular environment with intracellular networks (reviewed by Ingber, 2006; Friedland et al , 2009; Schwartz, 2010). They have previously been shown to be involved in lymph valve formation in vivo (Bazigou et al , 2009), and in lymphangiogenesis during various pathologies, such as inflammation, tumour growth, and wound healing (Hong et al , 2004; Kajiya et al , 2005; Chen et al , 2007; Dietrich et al , 2007; Okazaki et al , 2009; Garmy‐Susini et al , 2010). In addition, α5β1 integrin was shown to associate with VEGFR3 and to trigger its activation via c‐Src (Zhang et al , 2005; Galvagni et al , 2010).…”

“…Mechanical forces can therefore affect the entire cell via integrin‐mediated signalling (reviewed by Ingber, 2006; Papusheva and Heisenberg, 2010; Schwartz, 2010). The largest subgroup of heterodimeric integrins is that containing the β1 integrin, and several β1 integrins have been reported to participate in lymphatic development in the adult or late embryonic mouse (Hong et al , 2004; Kajiya et al , 2005; Chen et al , 2007; Dietrich et al , 2007; Bazigou et al , 2009; Okazaki et al , 2009; Garmy‐Susini et al , 2010). In addition, α5β1 integrins have been shown to exist in a complex with VEGFR3 (Zhang et al , 2005) and Tie2 (Cascone et al , 2005), thereby regulating endothelial cell responses to ECM and growth factors.…”

ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions

“…However, these are often not sufficient to achieve complete inhibition and may cause unwanted side effects such as cataracts or elevated intraocular pressure (15). While anti-(lymph)angiogenic therapies targeting the VEGF-A or VEGF-C signaling pathways (17, 37, 38) or the insulin receptor substrate-1 (39, 40) have been brought forward in many (pre)clinical studies as promising therapies in corneal allograft rejection, only few other targets have been described so far (19, 41, 42). Interestingly, another study recently demonstrated that blockade of CCL21/CCR7 signaling, i.e., the best described signaling axis supporting DC migration (43), promoted graft survival in a low-risk corneal transplantation setup (42).…”

Angiopoietin-2 Blockade Promotes Survival of Corneal Transplants

“…6 More recently, it was reported that anti-Ang-2 treatment reduced the number of macrophages in the corneas 10 days after suture placement. 10 Because macrophage infiltration peaks around 2 weeks after corneal transplanation, 11 we next evaluated the effect of Ang-2 blockade on corneal macrophages at 2 weeks after transplantation. As shown in Supplementary Figure S1, our results showed that Ang-2 blockade tended to reduce the number of macrophages inside the grafted corneas though the data were not statistically significant ( P = 0.9).…”

Mechanoinduction of lymph vessel expansion

“…β1 Integrins link the ECM with the actin cytoskeleton, thus connecting the extracellular environment with intracellular networks (reviewed by Ingber, 2006; Friedland et al , 2009; Schwartz, 2010). They have previously been shown to be involved in lymph valve formation in vivo (Bazigou et al , 2009), and in lymphangiogenesis during various pathologies, such as inflammation, tumour growth, and wound healing (Hong et al , 2004; Kajiya et al , 2005; Chen et al , 2007; Dietrich et al , 2007; Okazaki et al , 2009; Garmy‐Susini et al , 2010). In addition, α5β1 integrin was shown to associate with VEGFR3 and to trigger its activation via c‐Src (Zhang et al , 2005; Galvagni et al , 2010).…”

“…Mechanical forces can therefore affect the entire cell via integrin‐mediated signalling (reviewed by Ingber, 2006; Papusheva and Heisenberg, 2010; Schwartz, 2010). The largest subgroup of heterodimeric integrins is that containing the β1 integrin, and several β1 integrins have been reported to participate in lymphatic development in the adult or late embryonic mouse (Hong et al , 2004; Kajiya et al , 2005; Chen et al , 2007; Dietrich et al , 2007; Bazigou et al , 2009; Okazaki et al , 2009; Garmy‐Susini et al , 2010). In addition, α5β1 integrins have been shown to exist in a complex with VEGFR3 (Zhang et al , 2005) and Tie2 (Cascone et al , 2005), thereby regulating endothelial cell responses to ECM and growth factors.…”

ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions

“…However, these are often not sufficient to achieve complete inhibition and may cause unwanted side effects such as cataracts or elevated intraocular pressure (15). While anti-(lymph)angiogenic therapies targeting the VEGF-A or VEGF-C signaling pathways (17, 37, 38) or the insulin receptor substrate-1 (39, 40) have been brought forward in many (pre)clinical studies as promising therapies in corneal allograft rejection, only few other targets have been described so far (19, 41, 42). Interestingly, another study recently demonstrated that blockade of CCL21/CCR7 signaling, i.e., the best described signaling axis supporting DC migration (43), promoted graft survival in a low-risk corneal transplantation setup (42).…”

Angiopoietin-2 Blockade Promotes Survival of Corneal Transplants

“…6 More recently, it was reported that anti-Ang-2 treatment reduced the number of macrophages in the corneas 10 days after suture placement. 10 Because macrophage infiltration peaks around 2 weeks after corneal transplanation, 11 we next evaluated the effect of Ang-2 blockade on corneal macrophages at 2 weeks after transplantation. As shown in Supplementary Figure S1, our results showed that Ang-2 blockade tended to reduce the number of macrophages inside the grafted corneas though the data were not statistically significant ( P = 0.9).…”

Mechanoinduction of lymph vessel expansion

“…β1 Integrins link the ECM with the actin cytoskeleton, thus connecting the extracellular environment with intracellular networks (reviewed by Ingber, 2006; Friedland et al , 2009; Schwartz, 2010). They have previously been shown to be involved in lymph valve formation in vivo (Bazigou et al , 2009), and in lymphangiogenesis during various pathologies, such as inflammation, tumour growth, and wound healing (Hong et al , 2004; Kajiya et al , 2005; Chen et al , 2007; Dietrich et al , 2007; Okazaki et al , 2009; Garmy‐Susini et al , 2010). In addition, α5β1 integrin was shown to associate with VEGFR3 and to trigger its activation via c‐Src (Zhang et al , 2005; Galvagni et al , 2010).…”

“…Mechanical forces can therefore affect the entire cell via integrin‐mediated signalling (reviewed by Ingber, 2006; Papusheva and Heisenberg, 2010; Schwartz, 2010). The largest subgroup of heterodimeric integrins is that containing the β1 integrin, and several β1 integrins have been reported to participate in lymphatic development in the adult or late embryonic mouse (Hong et al , 2004; Kajiya et al , 2005; Chen et al , 2007; Dietrich et al , 2007; Bazigou et al , 2009; Okazaki et al , 2009; Garmy‐Susini et al , 2010). In addition, α5β1 integrins have been shown to exist in a complex with VEGFR3 (Zhang et al , 2005) and Tie2 (Cascone et al , 2005), thereby regulating endothelial cell responses to ECM and growth factors.…”

ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions

“…However, these are often not sufficient to achieve complete inhibition and may cause unwanted side effects such as cataracts or elevated intraocular pressure (15). While anti-(lymph)angiogenic therapies targeting the VEGF-A or VEGF-C signaling pathways (17, 37, 38) or the insulin receptor substrate-1 (39, 40) have been brought forward in many (pre)clinical studies as promising therapies in corneal allograft rejection, only few other targets have been described so far (19, 41, 42). Interestingly, another study recently demonstrated that blockade of CCL21/CCR7 signaling, i.e., the best described signaling axis supporting DC migration (43), promoted graft survival in a low-risk corneal transplantation setup (42).…”