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A role for antibodies to human leukocyte antigens, collagen-V, and K-?1-Tubulin in antibody-mediated rejection and cardiac allograft vasculopathy.

ABSTRACT: We determined the role of donor-specific antibodies (DSA) and antibodies (Abs) to self-antigens, collagen-V (Col-V), and K-?1-Tubulin (KAT) in pathogenesis of acute antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) after human heart transplantation (HTx).One hundred thirty-seven HTx recipients, with 60 early period (? 12 months) and 77 late period (>12 months), were enrolled in this study. Circulating DSA was determined using LUMINEX. Abs against Col-I, II, IV, V, and KAT were measured using ELISA. Frequency of CD4+T helper cells (CD4+Th) secreting interferon (IFN)-?, interleukin (IL)-5, -10, or -17 specific to self-antigens were determined using Enzyme Linked Immunosorbent Spot assay.A significant association between AMR and DSA was demonstrated. Development of DSA in AMR patients correlated well with the development of auto-Abs to Col-V (AMR[+]: 383 ± 72 ?g/mL, AMR[-]: 172 ± 49 ?g/mL, P=0.033) and KAT (AMR[+]: 252 ± 49 ?g/mL, AMR[-]: 61 ± 21 ?g/mL, P=0.014). Patients who developed AMR demonstrated increased frequencies of CD4+Th secreting IFN-? and IL-5 with reduction in IL-10 specific for Col-V/KAT. Patients diagnosed with CAV also developed DSA and auto-Abs to Col-V (CAV[+]: 835 ± 142 ?g/mL, CAV[-]: 242 ± 68 ?g/mL, P=0.025) and KAT (CAV[+]: 768 ± 206 ?g/mL, CAV[-]: 196 ± 72 ?g/mL, P=0.001) with increased frequencies of CD4+Th secreting IL-17 with reduction in IL-10 specific for Col-V/KAT. CONCLUSIONS.: Development of Abs to human leukocyte antigens and self-antigens are associated with increases in CD4+Th secreting IFN-? and IL-5 in AMR and IL-17 in CAV, with reduction in CD4+Th secreting IL-10 in both AMR and CAV.

SUBMITTER: Nath DS

PROVIDER: S-EPMC3722875 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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A role for antibodies to human leukocyte antigens, collagen-V, and K-α1-Tubulin in antibody-mediated rejection and cardiac allograft vasculopathy.

Nath Dilip S DS Tiriveedhi Venkataswarup V Basha Haseeb Ilias HI Phelan Donna D Moazami Nader N Ewald Gregory A GA Mohanakumar Thalachallour T

Transplantation 20110501 9

<h4>Background</h4>We determined the role of donor-specific antibodies (DSA) and antibodies (Abs) to self-antigens, collagen-V (Col-V), and K-α1-Tubulin (KAT) in pathogenesis of acute antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) after human heart transplantation (HTx).<h4>Methods</h4>One hundred thirty-seven HTx recipients, with 60 early period (≤ 12 months) and 77 late period (>12 months), were enrolled in this study. Circulating DSA was determined using LUMINEX. A ...[more]

PMID: 21383658

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Project description:Low levels of plasma adiponectin, an adipocytokine that possesses anti-inflammatory and antiatherogenic properties, frequently observed among obese subjects correlate with higher prevalence of several cardiovascular diseases. This study investigated whether adiponectin modulates allograft rejection in major histocompatibility complex class II-mismatched cardiac transplants.We heterotopically transplanted Bm12 allografts into adiponectin-deficient (APN-/-, C57BL/6 background) or wild-type (APN+/+) mice. Some APN-/- mice received adiponectin reconstitution by adenovirus. Histologic analyses assessed allograft rejection, and real-time reverse-transcriptase polymerase chain reaction evaluated the genes for cytokines/chemokines associated with the immune and inflammatory responses. In addition, we tested the effect of adiponectin on proliferation and cytokine/chemokine production in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.Allografts transplanted to APN-/- mice showed severe acute rejection relative to transplants in APN+/+ hosts accompanied by increased accumulation of CD4- and CD8-positive T lymphocytes and Mac3-positive macrophages. Adiponectin provision by adenovirus in APN-/- mice reversed these exacerbated responses to allografting. The rejected allografts in APN-/- mice contained significantly higher levels of tumor necrosis factor-alpha, interferon-gamma, and regulated on activation normal t expressed and presumably secreted. Moreover, adiponectin significantly suppressed proliferation and production of tumor necrosis factor-alpha, interferon-gamma, regulated on activation normal t expressed and presumably secreted, monocyte chemotactic protein-1, and interferon-gamma inducible protein-10 in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.These observations provide new mechanistic insight into immunoregulation in allograft recipients relative to obesity, an increasingly prevalent risk factor. Adiponectin may offer a new therapeutic target for allograft rejection after cardiac transplantation.

Project description:BackgroundThe association between genetic polymorphisms and early cardiac allograft vasculopathy (CAV) development is relatively unexplored. Identification of genes involved in the CAV process may offer new insights into pathophysiology and lead to a wider range of therapeutic options.MethodsThis prospective study of 109 patients investigated 44 single nucleotide polymorphisms (SNPs) within the susceptibility loci potentially related to coronary artery disease, carotid artery intima-media thickness (cIMT), and in nitric oxide synthase gene. Genotyping was done by the Fluidigm SNP Type assays and Fluidigm 48.48 Dynamic Array IFC. The intima thickness progression (IT) was evaluated by coronary optical coherence tomography performed 1 month and 12 months after heart transplantation (HTx).ResultsDuring the first post-HTx year, the mean intima thickness (IT) increased by 24.0 ± 34.2 µm (p < 0.001) and lumen area decreased by ‒0.9 ± 1.8 mm2 (p < 0.001). The rs1570360 (A/G) SNP of the vascular endothelial growth factor A (VEGFA) gene showed the strongest association with intima thickness progression, even in the presence of the traditional CAV risk factors. SNPs previously related to carotid artery intima-media thickness rs11785239 (PRAG1), rs6584389 (PAX2), rs13225723 (LINC02577) and rs17477177 (CCDC71L), were among the five most significantly associated with IT progression but lost their significance once traditional CAV risk factors had been added.ConclusionResults of this study suggest that genetic variability may play an important role in CAV development. The vascular endothelial growth factor A gene SNP rs1570360 showed the strongest association with intima thickness (IT) progression measured by OCT, even in the presence of the traditional CAV risk factors (Tab. 3, Fig. 3, Ref. 36). Text in PDF www.elis.sk Keywords: cardiac allograft vasculopathy, optical coherence tomography, vascular endothelial growth factor A, intimal thickening, genetic polymorphism.

Dataset Information

A role for antibodies to human leukocyte antigens, collagen-V, and K-?1-Tubulin in antibody-mediated rejection and cardiac allograft vasculopathy.

Publications

A role for antibodies to human leukocyte antigens, collagen-V, and K-α1-Tubulin in antibody-mediated rejection and cardiac allograft vasculopathy.

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