Donor MHC and adhesion molecules in transplant arteriosclerosis

Shi, Connie R.; Feinberg, Mark W.; Zhang, Dorothy; Patel, Anand; Sim, Chäng U.; Dong, Zhao; Chapman, Susan M.; Gutierrez‐Ramos, José Carlos; Wagner, Denisa D.; Sibinga, Nicholas E.S.; Haber, Edgar

doi:10.1172/jci4584

Cited by 28 publications

(18 citation statements)

References 37 publications

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“…IFN-γ also antagonizes the production of collagen, which is widely believed to stabilize plaque structure (2,22,26). Last, studies on transplant models of atherosclerosis also strongly support a role for IFN-γ, T cells, and B cells in atherogenesis (27,28). Intriguingly, these studies have demonstrated that T cell-secreted IFN-γ stimulates SMC proliferation through the upregulation of PDGF responses (29).…”

Section: Introductionmentioning

confidence: 91%

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Lymphocytes are important in early atherosclerosis

Song¹,

Leung²,

Schindler³

2001

J. Clin. Invest.

128

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Lymphocytes represent a potentially important proinflammatory cell that localizes to atherosclerotic lesions. To determine whether they contribute to lesion development, atherosclerosis-prone (LDLR -/-) mice were crossed with lymphocyte-deficient (RAG1 -/-) mice to generate double knockout progeny. After 8 weeks on a Western-type diet (WTD), lesion development was reduced by 54% in double knockout mice, as compared with matched LDLR -/-controls. However, these significant differences in lesion area gradually subsided as the WTD was continued for 12 and 16 weeks. Consistent with this observation, histological studies determined that lesion initiation and early progression were delayed in RAG1/LDL-R double knockout mice. Differences in lesion area did not correlate with any significant alterations in plasma lipid levels. These studies suggest that lymphocytes play an important role early in atherogenesis. mice were crossed with the RAG1-null mice, and atherogenesis was evaluated. Although atherosclerotic lesions were small after 4 weeks on a Western type diet (WTD), they had grown significantly by 8 weeks. Moreover, they were 54% smaller in the RAG1/LDL-R double knockout mice, suggesting lymphocyte function is important at this point in time. Lesions continued to grow with time, but the relative difference in lesion area between LDL-R-null and RAG1/LDL-R double knockout mice became less significant. These results indicate that lymphocytes play a more important role early in the pathogenesis of atherosclerotic lesions. MethodsMice. The LDL-R-null mice (in a C57BL/6 background) and RAG1-null mice (in a C57BL/6 background) were obtained from The Jackson Laboratory (Bar Harbor, Maine, USA). Mice, maintained in a specific pathogen-free facility, were interbred and genotyped by PCR as described previously (32-34). Once sufficient numbers of single-and double knockout mice were available (i.e., about ten age-and sex-matched mice for each group), they were placed on a WTD (21% fat, 0.15% cholesterol for 4-16 weeks; Harlan Teklad Laboratory, Winfield, Iowa, USA). Hearts and fasted plasma samples were collected from sacrificed mice.Histochemistry. Hearts were perfused with PBS, embedded in OCT, and snap-frozen. Then 10-µm-thick transverse sections covering 350-400 µm of the proximal aorta were collected. For atherosclerosis quantitation, every sixth section (for a total of six sections) was stained with Oil red O after fixation in 4% paraformaldehyde. Lesion area was then determined by measuring accumulated intimal lipid by video microscopy, as described previously (35-37). To evaluate lesion cellularity, nuclei were counted in serial sections that had been stained with Oil red O. Alternating sections were stained with either hematoxylin and eosin (H&E) or Trichrome after the fixation in 4% formaldehyde (22). Collagen content was determined by measuring the accumulated collagen in serial Trichrome-stained sections, as described above.Immunohistochemistry. Cold acetone fixed frozen sections were stained with an MHC-II-specif...

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Section: Introductionmentioning

confidence: 91%

“…Intriguingly, these studies have demonstrated that T cell-secreted IFN-γ stimulates SMC proliferation through the upregulation of PDGF responses (29). B cells also contribute to transplant atherosclerosis, but their role may be limited to antigen presentation (27).…”

Section: Introductionmentioning

confidence: 99%

Lymphocytes are important in early atherosclerosis

Song¹,

Leung²,

Schindler³

2001

J. Clin. Invest.

128

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“…Transforming growth factor (TGF)-␤1, a pleiotropic mediator, plays an important role in cell growth, differentiation, and activation in a number of immune and non-immune cell types (17)(18)(19). TGF-␤1 participates in the maintenance of self-tolerance and homeostasis of several T cell effectors including T regs (12,14,20).…”

Section: Cd25mentioning

confidence: 99%

Kruppel-like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25− T Cells and T Regulatory Cells

Cao

Wara

Icli

et al. 2009

Journal of Biological Chemistry

Self Cite

119

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“…Direct evidence that oxygen free radicals, adhesion molecules, and neutrophils play a role in the pathogenesis of CTD is shown by interference studies [29, 107, 2101. One recent study, for instance, revealed that carotid allografts from donor mice deficient in ICAM-1 had a 52 % reduction of intimal hyperplasia compared to controls [183].…”

Section: Endothelial Cell Activationmentioning

confidence: 99%

“…An indication that donor MHC class I and I1 antigens play a role in the chronic phase has recently been obtained. Carotid allografts from donor mice deficient in MHC I1 molecules showed a reduction of intimal hyperplasia formation of 33 %, primarily due to a reduction in smooth muscle cell accumulation [183]. The absence of such a continuous alloantigeneic stimulus in syngeneic transplants might explain the much more rapid development of CTD in allografts.…”

Section: Anti-donor Specific Antibodiesmentioning

confidence: 99%

Etiology and pathophysiology of chronic transplant dysfunction

Kouwenhoven

IJzermans

Bruin

2000

Transplant International

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Chronic transplant dysfunction (CTD) is the predominant cause of late graft failure. The common histopathological feature in all transplanted organs is intimal hyperplasia accompanied by organ specific lesions. The knowledge about CTD is incomplete, and there is no therapy to prevent or treat it. This review describes the current knowledge on the etiology of CTD, with emphasis on kidney transplants, and postulates a pathophysiologic route through which CTD may develop. The problem of chronic transplant dysfunctionSince it was first shown in 1954 that successful transplantation of a healthy kidney could completely rehabilitate an individual with renal failure, transplantation of several organs has become an increasingly successful medical treatment for patients with end-stage organ failure. In 1998, in the Eurotransplant area alone, more than 3000 kidneys, 750 hearts, about 1000 livers, 230 lungs, and about 100 pancreas from cadaveric donors were transplanted [9]. Worldwide, 56 intestinal transplantations were performed in 1996 [70]. The shortterm results after clinical organ transplantation have improved progressively. This is principally due to refinements in tissue typing, advancements in organ preservation, operative techniques and ancillary care, more effective immunosuppressive agents, and better monitoring after engraftment. For example, one year survival of cadaveric kidneys has increased from approximately 50 % by the end of the 1960 s, to about 85 % nowadays 1671, and for living-related kidneys from 80% to Despite improving early results, however, it has become clear that clinical transplantation has not achieved its goal as a long-term treatment. For the period beyond one year, the annual rate of graft loss has changed less since the beginning of the experience. The half-life of cadaveric kidney allografts, for instance, has remained consistent at 7.5-9.5 years, although the latest United States Renal Data System (USRDS) data suggest that half-life of first cadaveric kidney grafts is improving (Figure 1) [68, 1461. Similarly, the half-life beyond the first year of heart transplants is 10.5 years [146]. Other organ transplants generally show comparable results, with exception of the liver, which shows more favourable long-term results [lo, 981.

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Donor MHC and adhesion molecules in transplant arteriosclerosis

Cited by 28 publications

References 37 publications

Lymphocytes are important in early atherosclerosis

Lymphocytes are important in early atherosclerosis

Kruppel-like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25− T Cells and T Regulatory Cells

Etiology and pathophysiology of chronic transplant dysfunction

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