In Vivo Platelet–Endothelial Cell Interactions in Response to Major Histocompatibility Complex Alloantibody

Morrell, Craig N.; Murata, Kazunori; Swaim, Anne Marie; Mason, Emily; Martin, Tanika V.; Thompson, Laura E.; Ballard, Mathew; Fox-Talbot, Karen; Wąsowska, Barbara; Baldwin, William M.

doi:10.1161/circresaha.107.170332

Cited by 68 publications

(75 citation statements)

References 32 publications

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“…In the early 1990s, clinicopathologic observations led to the recognition of histopathological features of acute ABMR in kidney (3,4), followed by discovery of C4d staining (5 (8,9) or noncomplement activating DSA (10)(11)(12) (27) (32). (38).…”

Section: Abmr: An Underestimated Problem In Allografts Robert Colvin mentioning

confidence: 99%

Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups

Sis

Mengel

Haas

et al. 2010

American Journal of Transplantation

703

595

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The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v-lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics-technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

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Section: Abmr: An Underestimated Problem In Allografts Robert Colvin mentioning

confidence: 99%

Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups

Sis

Mengel

Haas

et al. 2010

American Journal of Transplantation

703

595

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“…3,25 Plasma was collected on multiple days, and plasma PF4 was measured to determine whether platelets are activated during the VSMC injury response. Plasma PF4 levels were increased in control IgG-treated mice ( Figure 1A), indicating ongoing platelet activation.…”

Section: Platelets Promote Early Inflammatory Responses To Vascular Imentioning

confidence: 99%

“…Platelets not only adhere to a damaged vessel wall but also adhere to an intact inflamed endothelium without forming an obstructive thrombus, such as at sites of atherosclerotic lesion development and transplant endothelium. [3][4][5][6] Platelet-derived inflammatory mediators include adhesion molecules (integrins, P-selectin), secreted small molecules (ADP, thromboxane, serotonin), chemokines, and cytokines. Major platelet-derived chemokines and cytokines include platelet factor 4 (PF4/CXCL4), proplatelet basic protein and its breakdown products b-thromboglobulin/NAP-2/CXCL7, RANTES/CCL5, interleukin (IL)-1a, IL-1b, IL-8, and transforming growth factor-beta.…”

Section: Introductionmentioning

confidence: 99%

Platelet factor 4 mediates vascular smooth muscle cell injury responses

Shi

Field

Long

et al. 2013

Blood

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Key Points• PF4 mediates VSMC injury responses.• PF4-driven effects are, in part, KLF4 dependent.Activated platelets release many inflammatory molecules with important roles in accelerating vascular inflammation. Much is known about platelet and platelet-derived mediator interactions with endothelial cells and leukocytes, but few studies have examined the effects of platelets on components of the vascular wall. Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to injury including the production of inflammatory molecules, cell proliferation, cell migration, and a decline in the expression of differentiation markers. In this study, we demonstrate that the platelet-derived chemokine platelet factor 4 (PF4/CXCL4) stimulates VSMC injury responses both in vitro and in vivo in a mouse carotid ligation model. PF4 drives a VSMC inflammatory phenotype including a decline in differentiation markers, increased cytokine production, and cell proliferation. We also demonstrate that PF4 effects are mediated, in part, through increased expression of the transcription factor Krüppel-like factor 4. Our data indicate an important mechanistic role for platelets and PF4 in VSMC injury responses both in vitro and in vivo. (Blood. 2013;121(21):4417-4427)

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“…The clinical relevance and mechanisms for how alloantibodies can contribute to allograft rejection in the absence of complement activation, such as in the case of low-level HLA antibodies, are currently under investigation. 5,6 Reports of allograft rejection in HLA identical sibling transplants suggest a role for non-HLA antibodies in some rejections. 7,8 Non-HLA antigens that have been associated with renal allograft rejection include agrin, vimentin, perlecan, Ka-tubulin, protein kinase Cz, major histocompatibility complex class Irelated chain A, and angiotensin II type 1 receptor.…”

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confidence: 99%

Endothelial Cell Antibodies Associated with Novel Targets and Increased Rejection

Jackson¹,

Sigdel

Delville

et al. 2015

Journal of the American Society of Nephrology

112

107

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The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24% of pretransplant sera, and they were associated with post-transplant donorspecific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.

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In Vivo Platelet–Endothelial Cell Interactions in Response to Major Histocompatibility Complex Alloantibody

Abstract: Abstract-Platelets

Cited by 68 publications

References 32 publications

Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups

Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups

Platelet factor 4 mediates vascular smooth muscle cell injury responses

Endothelial Cell Antibodies Associated with Novel Targets and Increased Rejection

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