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Expert Review of Clinical Immunology 01/2013; 9(1):5-7. · 2.07 Impact Factor
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ABSTRACT: Transplant arteriosclerosis (TA) restricts long-term survival of heart transplant recipients. Although the role of monocyte/macrophages is well established in native atherosclerosis, it has been studied to a much lesser extent in TA. Plasma cholesterol is the most important non-immunologic risk factor for development of TA but the underlying mechanisms are largely unknown. We hypothesized that monocyte/macrophages might play an important role in the pathogenesis of TA under hyperlipidemic conditions.
We studied TA in fully mismatched arterial allografts transplanted into hyperlipidemic ApoE(-/-) recipients compared to wild-type controls. The recruitment of distinct monocyte populations into the grafts was tracked by in vivo labelling with fluorescent microspheres. We used antibody-mediated depletion protocols to dissect the relative contribution of T lymphocytes and monocytes to disease development.
In the hyperlipidemic environment the progression of TA was highly exacerbated and the inflammatory CD11b(+)CD115(+)Ly-6C(hi) monocytes were preferentially recruited into the neointima. The number of macrophage-derived foam cells present in the grafts strongly correlated with plasma cholesterol and disease severity. Depletion of Ly-6C(hi) monocytes and neutrophils significantly inhibited macrophage accumulation and disease progression. The accelerated monocyte recruitment occurs through a T cell-independent mechanism, as T cell depletion did not influence macrophage accumulation into the grafts.
Our study identifies for the first time the involvement of inflammatory Ly-6C(hi) monocytes into the pathogenesis of TA, particularly in conditions of hyperlipidemia. Targeted therapies modulating the recruitment and activation of these cells could potentially delay coronary allograft vasculopathy and improve long-term survival of heart transplant recipients.
Atherosclerosis 05/2012; 223(2):291-8. · 3.79 Impact Factor
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ABSTRACT: Regulatory T cells (T(regs)) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring T(regs), an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of total T cell populations with defined allogeneic antigen-presenting cells (APCs) under conditions that lead to the generation or expansion of donor-reactive, adaptive T(regs). Here we demonstrate that stimulation of mouse CD4(+) T cells by immature allogeneic dendritic cells combined with pharmacological inhibition of phosphodiesterase 3 (PDE) resulted in a functional enrichment of Foxp3(+) T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated by polyclonal CD4(+) effectors or donor-reactive CD8(+) T cell receptor transgenic T cells and inhibited both effector cell proliferation and T cell priming for interferon-γ production. Notably, PDE inhibition also enhanced the enrichment of human Foxp3(+) CD4(+) T cells driven by allogeneic APCs. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assay and, moreover, attenuated the development of vasculopathy mediated by autologous peripheral blood mononuclear cells in a functionally relevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graft-reactive, functional mouse and human T(regs) that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for T(reg)-based therapies.
Science translational medicine 05/2011; 3(83):83ra40. · 7.80 Impact Factor
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ABSTRACT: Transplant arteriosclerosis is the hallmark of chronic allograft dysfunction (CAD) affecting transplanted organs in the long term. These fibroproliferative lesions lead to neointimal thickening of arteries in all transplanted allografts. Luminal narrowing then leads to graft ischemia and organ demise. To date, there are no known tolerance induction strategies that prevent transplant arteriosclerosis. Therefore, we designed this study to test the hypothesis that human regulatory T cells (T(reg) cells) expanded ex vivo can prevent transplant arteriosclerosis. Here we show the comparative capacity of T(reg) cells, sorted via two separate strategies, to prevent transplant arteriosclerosis in a clinically relevant chimeric humanized mouse system. We found that the in vivo development of transplant arteriosclerosis in human arteries was prevented by treatment of ex vivo-expanded human T(reg) cells. Additionally, we show that T(reg) cells sorted on the basis of low expression of CD127 provide a more potent therapy to conventional T(reg) cells. Our results demonstrate that human T(reg) cells can inhibit transplant arteriosclerosis by impairing effector function and graft infiltration. We anticipate our findings to serve as a foundation for the clinical development of therapeutics targeting transplant arteriosclerosis in both allograft transplantation and other immune-mediated causes of vasculopathy.
Nature medicine 07/2010; 16(7):809-13. · 27.14 Impact Factor
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ABSTRACT: Transplantation is the most effective treatment for end-stage organ failure, but organ survival is limited by immune rejection and the side effects of immunosuppressive regimens. T cells are central to the process of transplant rejection through allorecognition of foreign antigens leading to their activation, and the orchestration of an effector response that results in organ damage. Long-term transplant acceptance in the absence of immunosuppressive therapy remains the ultimate goal in the field of transplantation and many studies are exploring potential therapies. One promising cellular therapy is the use of regulatory T cells to induce a state of donor-specific tolerance to the transplant. This article first discusses the role of T cells in transplant rejection, with a focus on the mechanisms of allorecognition and the alloresponse. This is followed by a detailed review of the current progress in the field of regulatory T-cell therapy in transplantation and the translation of this therapy to the clinical setting.
Expert Review of Clinical Immunology 01/2010; 6(1):155-69. · 2.07 Impact Factor
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ABSTRACT: In recent years there has been increased interest in understanding the physiology and function of regulatory T cells. In this review we focus on the characterization of regulatory T-cell subsets and their potential therapeutic use in organ transplantation.
Regulatory T cells can play an instrumental role in the establishment of operational tolerance to allografts. The level of expression and the extent of posttranslational acetylation of the regulatory T-cell specific transcription factor Foxp3 are important modulators of their suppressive activity. Low expression of CD127 can be used as a novel marker to define pure regulatory T-cell populations and the expression of CD45RA on CD4CD25 regulatory T cells characterizes a population with a more stable phenotype upon expansion in vitro. Interleukin-35 is a recently discovered immunosuppressive cytokine secreted by CD4CD25 regulatory T cells. Although the presence of allospecific memory T cells in the pretransplant period and the use of immunosuppressants might interfere with the effectiveness of regulatory T-cell-based therapies, encouraging results indicate that the immunosuppressive drug rapamycin does not affect the expansion and function of regulatory T cells and could be included in a combined therapy.
Important advances have been made towards establishing regulatory T cells as a viable therapy in transplantation and the first clinical trials using human regulatory T cells are currently underway. There are, however, important limitations and safety issues that have to be addressed before this therapy can be fully translated into the clinic.
Current opinion in organ transplantation 09/2008; 13(4):333-8. · 1.22 Impact Factor
