T lymphocytes inhibit the vascular response to injury.

Abstract

The proliferation of vascular smooth muscle cells is controlled by specific growth factors and cytokines acting in paracrine networks. Macrophage products such as the platelet-derived growth factor and interleukin 1 promote smooth muscle proliferation and are released in the arterial wall during atherosclerosis and repair processes. T lymphocytes are also present in vascular tissue, but their role in vascular growth control in vivo has been unclear. We now demonstrate that rats in which T lymphocytes have been eliminated by a monoclonal antibody develop larger proliferative arterial lesions after balloon-catheter injury. Larger lesions also develop in athymic rnu/rnu rats that lack T lymphocytes, when compared with rnu/+ littermates with normal T-cell levels. Finally, injection of the lymphokine interferon y inhibits smooth muscle proliferation and results in smaller lesions compared with controls injected with buffer alone. These results indicate that T lymphocytes modulate smooth muscle proliferation during vascular repair. We propose that T lymphocytes may play an important, immunologically nonspecific role in tissue repair processes.The proliferation of vascular smooth muscle cells (SMC) is controlled by specific growth factors and cytokines acting in paracrine networks (1-4). It was previously thought that the major growth-regulating factors were released by platelets adhering to deendothelialized arterial surfaces, but inflammatory cells may be equally important as growth regulators for SMC (2-4).Macrophage products, such as the platelet-derived growth factor and interleukin 1, promote SMC proliferation in cell culture (1,2,5,6) and are expressed in the arterial wall during atherosclerosis and repair processes after experimental injury (7-10). T lymphocytes are also present in vascular tissue during atherosclerosis and vascular repair (3,(11)(12)(13)(14), but their role in vascular growth control in vivo has been unclear. We have previously found that the T-lymphocyte product interferon y (IFN-'y) inhibits SMC proliferation (15, 16); this finding would point toward a growth-inhibitory role of T lymphocytes in vascular repair. It was, however, also found that the immunosuppressive drug cyclosporin A inhibits development of a proliferative lesion after injury to rat arteries, which could imply a growth-promoting effect of T cells (17). Whether T cells promote or inhibit SMC proliferation in vivo was, therefore, unclear. We have now attempted to determine the role of T lymphocytes in the vascular response to injury in vivo by using T-cell-deficient rats.Proliferation of SMC can be studied in vivo by using a catheter to remove the endothelial lining of a carotid artery segment in the rat. This procedure results in SMC migration from the medial to intimal layer of the artery, SMC proliferation in the intima, and formation of an intimal lesion that reduces the size of the arterial lumen (18). The lesions are dominated by SMC, but a few monocyte-derived macrophages and T lymphocytes are also present (13)....

CD4 Cell Lymphopenia and Atherosclerosis in Renal Transplant Recipients

“…Furthermore, Nilsson et al (6) demonstrated a 58% decrease in degree of atherosclerosis in rabbits immunized against oxidized or native LDL. Other animal studies have also suggested that T lymphocytes may have a protective role against atherosclerosis progression (7). Rats in which T lymphocytes have been eliminated by a monoclonal antibody treatment develop larger proliferative arterial lesions after balloon-catheter injury.…”

Immunization of LDL Receptor–Deficient Mice With Homologous Malondialdehyde-Modified and Native LDL Reduces Progression of Atherosclerosis by Mechanisms Other Than Induction of High Titers of Antibodies to Oxidative Neoepitopes

“…For example, elimination of T lymphocytes with monoclonal antibodies resulted in larger proliferative lesions in balloon-catheterized rat aortas. 45 Cyclosporine treatment (which suppresses T cells) of hypercholesterolemic mice and rabbits also accelerated atherosclerosis. 46,47 MHC class I-deficient C57BL/6 mice, which lack cytolytic T cells and have impaired natural killer cell activity, also developed a 3-fold increase in lesions in the aortic valve region when fed a high-fat diet.…”

Effect of Cyclosporine on Arterial Balloon Injury Lesions in Cholesterol-Clamped Rabbits

“…In addition, the scarce presence of T lymphocytes in the neointima formed as a consequence of balloon injury would not suggest that these cells would have a major impact on this type of lesion. Results from studies using athymic nude rats 46,47 or T lymphocyte-depleted rats 46 have given equivocal results concerning the role of T lymphocytes in the pathogenic process of balloon injury-induced neointimal proliferation. Thus, present and previous results taken together do not support a significant influence of T lymphocytes on neointimal proliferation in the artery after balloon injury.…”