Role of Platelet-derived Growth Factor in Obliterative Bronchiolitis (Chronic Rejection) in the Rat

Kallio, Erkki; Koskinen, Petri; Aavik, Einari; Buchdunger, Elisabeth; Lemström, Karl

doi:10.1164/ajrccm.160.4.9802006

Cited by 45 publications

(35 citation statements)

References 25 publications

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“…34,35 Moreover, a wide array of profibrotic cytokines in addition to TGF-␤1, such as platelet-derived growth factor, has been linked to the pathogenesis of OB. 36 In summary, our observations establish that Smad3 is an essential, novel component of the fibroproliferative response in experimental OB wherein TGF-␤1 and CTGF are abundantly expressed. Disruption of Smad3 gene expression ameliorates obliterative airway disease, in part, through a reduction in collagen and fibronectin deposition.…”

Section: Discussionmentioning

confidence: 52%

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Ramirez

Takagawa

Sekosan

et al. 2004

The American Journal of Pathology

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Chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the single greatest impediment to long-term survival after lung transplantation. Transforming growth factor-␤1 (TGF-␤1) has been implicated in the tissue remodeling response associated with OB. Therefore, its intracellular signal transducer, Smad3, is a prime target of investigation. Herein, we examine the role of TGF-␤1, through Smad3, in the development of OB using heterotopic tracheal transplantation in wild-type and Smad3-null mice. TGF-␤1 was detectable within infiltrating mononuclear cells early after transplantation. Throughout the last 20 years, lung transplantation has evolved into an accepted treatment option for patients with end-stage lung disease because of emphysema, pulmonary fibrosis, pulmonary hypertension, and cystic fibrosis. 1 However, chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the major obstacle to long-term survival after lung transplantation. 2 Clinically, OB is characterized by airflow limitation, defined by a 20% decline in forced expiratory volume in 1 second (FEV 1 ), and is often complicated by recurrent lower respiratory tract infections. The histological hallmark of OB is the presence of obstructing intraluminal polyps comprised of fibromyxoid granulation tissue and plaques of dense submucosal eosinophilic scar on lung biopsy. OB can complicate up to 60% of lung allografts and becomes increasingly prevalent the further removed from the transplant operation. 3 Progressive OB ultimately results in worsening hypoxemia and death.Many studies on the pathogenesis of OB have concentrated on the role of cellular allogenic immune responses during OB development. However, fibroproliferation and tissue remodeling clearly play an important role in its pathogenesis because OB is characterized by the accumulation of fibroblasts and the excessive deposition of connective tissue matrix within the lumen of the affected bronchioles. The factors that initiate and maintain fibroproliferation and tissue remodeling within the airway lumen in OB have not been fully elucidated. One candidate factor is transforming growth factor (TGF)-␤, a pleiotropic cytokine with potent profibrotic activities. 4 Extensively studied in solid organ transplantation, TGF-␤ has been found to have beneficial effects on alloimmunity. For instance, overexpression of a TGF-␤ transgene leads to marked reductions in acute rejection and prolongation of graft survival in experimental heart and

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Section: Discussionmentioning

confidence: 52%

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Ramirez

Takagawa

Sekosan

et al. 2004

The American Journal of Pathology

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“…Monokine induced by IFN-␥ and IFN-␥-inducible protein-10 production in allograft tissue have been implicated in the recruitment of T cells to allografts via binding of these chemokines to CXCR3, leading to subsequent destruction of the transplanted tissues, including airways (20,21). Finally, TNF-␣ and IFN-␥ may directly stimulate fibroblasts present in the rejecting graft tissues, inducing their proliferation and elaboration of destructive effector activities, such as platelet-derived growth factor, a cytokine implicated in the development of OAD (4,22,23). Neutralization of TNF-␣ with either a soluble form of the TNF receptor or Ab has been shown to delay OAD in the mouse heterotopic tracheal transplant model of lung transplantation (24,25).…”

Section: Discussionmentioning

confidence: 99%

Trachea Allograft Class I Molecules Directly Activate and Retain CD8+ T Cells That Cause Obliterative Airways Disease

Richards

Dalheimer

Hertz

et al. 2003

The Journal of Immunology

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Human T cells responding against transplanted allogeneic lung tissue have been implicated in late graft failure secondary to obliterative bronchiolitis. This obliterative airways disease (OAD) also develops in heterotopic murine tracheal allografts in association with graft infiltration by both CD8+ and CD4+ T cells. To date, there has been little evidence to suggest that directly alloreactive CD8+ T cells either promote chronic rejection or lead to the development of OAD following airway allotransplantation. Using Ld-specific TCR-Tg 2C CD8+ T cells adoptively transferred into wild-type B6 (H-2b) mice and the transplantation of BALB/c (H-2d) tracheal allografts, we now show that the direct recognition of donor-specific class I MHC molecules by host CD8+ T cells leads to their activation, clonal expansion within the graft, and differentiation to an effector phenotype with the capacity to induce airway fibrosis. In addition, these experiments demonstrate that ongoing direct alloantigen recognition within the transplanted airway tissue is necessary for the recruitment and retention of these directly alloreactive CD8+ T cells. Thus, these experiments are the first to definitively show a role for directly alloreactive CD8+ T cells in the chronic rejection that leads to OAD.

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“…Production of TNF-␣ and IFN-␥ has, in fact, been observed in bronchoalveolar lavage fluid from patients undergoing lung rejection after allotransplantation and within the heterotopic tracheal allografts themselves (36 -40). Such CD4 ϩ T cell-derived lymphokines might activate and/or recruit those cells that are ultimately responsible for the production of the fibrosis-inducing cytokine platelet-derived growth factor, a fibroblast growth factor implicated in the pathogenesis of OAD (6,41). Immunohistochemistry studies have shown that both macrophages and alveolar epithelial cells can be important sources of platelet-derived growth factor within pulmonary tissue (6,42).…”

Section: T Cells Cooperate In the Induction Of Oadmentioning

confidence: 99%

Indirect Minor Histocompatibility Antigen Presentation by Allograft Recipient Cells in the Draining Lymph Node Leads to the Activation and Clonal Expansion of CD4+ T Cells That Cause Obliterative Airways Disease

Richards

Dalheimer

Ehst

et al. 2004

The Journal of Immunology

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Ag recognition by OVA-reactive OT-II (I-Ab restricted) and DO11.10 (I-Ad restricted) TCR-Tg CD4+ T cells after heterotopic transplantation of OVA transgene-expressing tracheal grafts was examined as a model of minor histocompatibility Ag (mHAg)-induced chronic allograft rejection. In response to airway allotransplantation with grafts expressing the OVA transgene, these TCR-Tg CD4+ T cells expressed the activation markers CD69 and CD44, demonstrated evidence of blastogenesis, underwent multiple rounds of cell division leading to their clonal expansion in the draining lymph node, and proceeded to differentiate to a effector/memory T cell phenotype based on a reduction in the expression of CD45RB. These mHAg-specific TCR-Tg CD4+ T cells responded equally well to fully MHC-mismatched tracheas and to class II-deficient allografts, demonstrating that donor mHAg recognition by recipient CD4+ T cells does not rely on Ag presentation by donor-derived APC. The activation of mHAg-specific TCR-Tg CD4+ T cells after their adoptive transfer into recipient mice given MHC-matched, but mHAg-disparate, airway allografts was associated with their movement into the allograft and the near uniform destruction of the transplanted airway tissue secondary to the development of obliterative airways disease. These results demonstrate that an activation of mHAg-reactive CD4+ T cells in the draining lymph node by recipient APC that indirectly express graft mHAg-derived peptide/class II MHC complexes precedes responder T cell proliferation and differentiation, and leads to the eventual migration of these alloreactive T cells to the transplanted airway tissue and the promotion of chronic graft rejection.

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Role of Platelet-derived Growth Factor in Obliterative Bronchiolitis (Chronic Rejection) in the Rat

Cited by 45 publications

References 25 publications

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Trachea Allograft Class I Molecules Directly Activate and Retain CD8+ T Cells That Cause Obliterative Airways Disease

Indirect Minor Histocompatibility Antigen Presentation by Allograft Recipient Cells in the Draining Lymph Node Leads to the Activation and Clonal Expansion of CD4+ T Cells That Cause Obliterative Airways Disease

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