Mechanisms of chronic rejection

Waaga, Ana Maria; Gasser, Martin; Laskowski, Igor; Tilney, Nicholas L.

doi:10.1016/s0952-7915(00)00132-1

Cited by 66 publications

(45 citation statements)

References 50 publications

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“…Graft loss occurring in the late period is predominantly due to the development of transplant arteriosclerosis (TA) in the graft arteries. 1,2 TA is histopathologically characterized by formation of a diffuse neointima in the graft arteries that consists mainly of smooth muscle cells (SMCs). 1,2 It is known that multifactorial events are involved in the pathogenesis of TA, both immunologic and nonimmunologic factors such as ischemia/reperfusion injury.…”

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“…1,2 TA is histopathologically characterized by formation of a diffuse neointima in the graft arteries that consists mainly of smooth muscle cells (SMCs). 1,2 It is known that multifactorial events are involved in the pathogenesis of TA, both immunologic and nonimmunologic factors such as ischemia/reperfusion injury. 3 Hence, neointima is formed through diverse events occurring in transplants, and proliferation of SMCs is considered a key event for TA development.…”

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confidence: 99%

“…3 Hence, neointima is formed through diverse events occurring in transplants, and proliferation of SMCs is considered a key event for TA development. 2 Conventionally, the medial vascular SMCs in grafts (donor-derived) have been thought to proliferate and migrate into the intima during the process of TA. 4 Refuting this wisdom, recent studies have demonstrated that the majority of neointimal SMCs are of host but not donor origin.…”

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Stromal Cell–Derived Factor-1 and CXCR4 Interaction Is Critical for Development of Transplant Arteriosclerosis

et al. 2004

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Background-Posttransplant chronic allograft deterioration associated with development of transplant arteriosclerosis (TA) remains an unresolved problem. Recent studies suggest that the smooth muscle cells (SMCs) constituting the neointima are derived from recipient hematopoietic stem cells (HSCs). However, the underlying mechanisms of the process are not yet fully elucidated. Methods and Results-We examined the genes expressed in allografts at different stages of TA development using a mice aortic transplantation model. Genes were analyzed by a differential mRNA display technique. We show that stromal cell-derived factor-1␣ (SDF-1␣) is a critical molecular target for the treatment of TA. During the course of TA, intragraft SDF-1␣ expression was upregulated with time, and the circulating HSCs expressing its counterreceptor CXCR4 increased in the recipients receiving allografts. CXCR4-positive HSCs, derived from transplant recipients, migrated into allografts via microvessels in the adventitia and then toward the luminal side. The HSCs differentiated into SMC-like cells, contributing to the in situ formation of the neointima. In support of a functional role for these molecules, in vivo neutralization of SDF-1␣ inhibited HSC mobilization and significantly attenuated neointimal formation. Conclusions-Interaction between SDF-1␣ and CXCR4 plays a key role in TA development. Blockade of SDF-1␣ may become a new therapeutic modality for TA.

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Stromal Cell–Derived Factor-1 and CXCR4 Interaction Is Critical for Development of Transplant Arteriosclerosis

et al. 2004

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“…6,8 A well-established model to study CR in renal allografts is the F344 to LEW rat model. All LEW recipients of F344 grafts develop acute rejection at approximately day 30 resulting in 50% graft loss.…”

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“…7 Moreover, transfer of posttransplantation (Tx) IgG antibodies or antigen-reactive immune serum into transplanted SCID mice results in transplant atherosclerosis. 6,8 A well-established model to study CR in renal allografts is the F344 to LEW rat model. All LEW recipients of F344 grafts develop acute rejection at approximately day 30 resulting in 50% graft loss.…”

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Antibody Response Against Perlecan and Collagen Types IV and VI in Chronic Renal Allograft Rejection in the Rat

Joosten

Dixhoorn

Borrias

et al. 2002

The American Journal of Pathology

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Chronic rejection is the leading cause of late renal transplant failure. Various structural lesions are observed in grafts undergoing chronic rejection including glomerular basement membrane (GBM) duplications. The well-established Fisher (F344) to Lewis (LEW) rat renal transplant model for chronic rejection was used to assess the presence and role of the humoral immune response against graft antigens during chronic rejection. LEW recipients of F344 allografts develop transplant glomerulopathy and produce IgG1 antibodies directed against F344 GBM preparations that are detectable 3 weeks after transplantation. Glomerular IgG1 deposition was observed that in vitro co-localized with a rabbit anti-rat GBM antiserum in rejecting F344 grafts; elution experiments of isolated glomeruli yielded IgG1 antibodies reactive in vitro with F344 GBM, but not LEW GBM. 1 The glomeruli may show a myriad of lesions, including chronic transplant glomerulopathy, which is characterized by duplication of the glomerular basement membrane (GBM) with interposition of electron-lucent material.2,3 Transplant glomerulopathy is observed in up to 20% of kidney grafts with CR. 4 It has been postulated that CR results from immune reactions of the recipient against yet poorly defined antigens exposed in the graft. 5 Nonimmune factors, such as hypertension or ischemia/reperfusion injury, may lead to unmasking or alteration of graft antigen(s).1 In syngeneic transplants with comparable degrees of nonimmune injury, CR does not develop within the same time span compared with allogeneic grafts, underlining the importance of immunological mechanisms.6 -8 We hypothesize that immune reactions such as antibody formation after previous damage play a role in the perpetuation of CR in renal allografts. In a mouse model of chronic cardiac graft rejection, antibodies are crucial for disease development.7 Immunoglobulin heavy chain (IGH) knockout mice that receive a cardiac allograft do not develop CR in contrast to immunoglobulin heavy chain wild-type mice.7 Moreover, transfer of posttransplantation (Tx) IgG antibodies or antigen-reactive immune serum into transplanted SCID mice results in transplant atherosclerosis. 6,8 A well-established model to study CR in renal allografts is the F344 to LEW rat model. All LEW recipients of F344 grafts develop acute rejection at approximately day 30 resulting in 50% graft loss. The surviving animals show histopathological and functional characteristics of CR from day 50. The reverse combination, ie, LEW kidneys transplanted into F344 rats all exhibit long-term surviving kidney grafts in the absence of histological abnormalities, despite early acute rejection episodes. In this model, antibody responses specific for lymph node-derived lymphocytes have been described. 9 These antibodies disappeared at 8 weeks after Tx and were described to

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