CD4+25+ Regulatory T Cells Limit Th1-Autoimmunity by Inducing IL-10 Producing T Cells Following Human Lung Transplantation

Bharat, Ankit; Fields, Ryan C.; Steward, Nancy; Trulock, Elbert P.; Patterson, G. Alexander; Mohanakumar, Thalachallour

doi:10.1111/j.1600-6143.2006.01383.x

Cited by 91 publications

(114 citation statements)

References 57 publications

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“…Therefore, we must consider the unique collaboration that exists between human memory Th-17 cells and CD14 1 macrophages as a possible link between adaptive and innate immunity. Bharat and colleagues, using PBMCs from patients who had received a lung transplant, demonstrated a key role for immune regulation by CD4 1 CD25 1 T-regulatory cells in preventing outgrowth of col(V)-reactive Th-1 (IFN-g) effector cells in long-term cultures (31,32). However, this report did not address the mechanisms of T-effector function in vivo or the role of IL-17.…”

Section: Discussionmentioning

confidence: 81%

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

Bobadilla¹,

Love²,

Jankowska‐Gan³

et al. 2008

Am J Respir Crit Care Med

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Rationale: The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col [V]), stimulates IL-17-dependent cellular immunity after lung transplantation. Objectives: To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD. Methods: Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa O 2 /FI O 2 index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity. Measurements and Main Results: We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4 + T-cell and monocyte mediated, and dependent on IL-17, IL-1b, and tumor necrosis factor (TNF)-a. Pa O 2 /FI O 2 indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa O 2 /FI O 2 , increased local TNF-a and IL-1b production, and a moderate-to-severe bronchiolitis/ vasculitis when compared with control isografts. Conclusions: The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.Keywords: lung transplantation; primary graft dysfunction; collagen type V; autoimmunity; memory T cellThe historic paradigm of allograft failure due primarily to humoral and cell-mediated immune responses to foreign major histocompatability complex (MHC) antigens has recently been challenged by additional hypotheses (1-3). Although it is clear that immunity to donor human leukocyte antigen (HLA) serves a significant role in mediating allograft rejection, recent evidence suggests that self-antigens exposed during ischemiareperfusion injury may, under some circumstances, present an equal, if not greater, barrier to graft acceptance (4-6). In lung transplantation, one such cryptic self-antigen is collagen type-V (col[V]) (2). Col(V) is classified as a minor fibrillar collagen and, in the human lung, the ratio of matrix collagens is 86:28:8:1.6 (for collagens I, III, IV, and V, respectively) (7). Under normal physiologic conditions, col(V) coassembles into heterotypic fibrils with the major fibrillar collagen type I (8, 9). In fact, the majority of the col(V) monomer is normally partitioned ...

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Section: Discussionmentioning

confidence: 81%

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

Bobadilla¹,

Love²,

Jankowska‐Gan³

et al. 2008

Am J Respir Crit Care Med

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“…Recent studies by Wilkes have demonstrated that immune responses against collagen V, an auto-Ag, can induce obliterative airway disease in rats following lung transplantation (32) and may also play a pathogenic role in BOS following human lung transplantation. Our studies have shown that collagen V-reactive cells develop during post-lung transplantation in humans and they are regulated by IL-10-producing T regulatory cells (35). The inflammatory status observed during the development of BOS in these patients could also result in the development of polyreactive Abs that recognize the self-Ags.…”

Section: Discussionmentioning

confidence: 98%

De Novo Production of K-α1 Tubulin-Specific Antibodies: Role in Chronic Lung Allograft Rejection

Goers¹,

Ramachandran²,

Aloush

et al. 2008

The Journal of Immunology

181

197

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Lung transplantation is the treatment option for a variety of end-stage pulmonary diseases. Posttransplant development of Abs against donor HLA and non-HLA Ags have been associated with acute and chronic rejection of transplanted organs. Development of bronchiolitis obliterans syndrome (BOS) following lung transplantation has been correlated with de novo production of anti-donor-HLA Abs. However, only a portion of the patients with BOS demonstrate detectable anti-donor-HLA Abs. Airway epithelium is considered as a major target for lung allograft rejection. In this study we demonstrate that many BOS+ patients (12 of 36) develop Abs reactive to epithelial cell Ag that are distinct from HLA. Furthermore, de novo production of antiepithelial cell Ab precedes clinical onset of BOS. N-terminal sequencing and blastx analysis as well as blocking with K-α1 tubulin-specific Ab identified the epithelial Ag as K-α1 tubulin. Binding of the de novo-produced anti-K-α1 tubulin Abs to the airway epithelial cells resulted in the increased expression of transcription factors (TCF5 and c-Myc), leading to increased expression of fibrogenic growth factors, activation of cell cycle signaling, and fibroproliferation, the central events in immunopathogenesis of BOS following human lung transplantation.

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“…Islets from murine pancreata were isolated and transplanted as described in our earlier publicaions (18,19 (20,21 (22). …”

Section: Mouse Islet Isolation Transplant and Immunosuppressionmentioning

confidence: 99%

Activated Effector and Memory T Cells Contribute to Circulating sCD30: Potential Marker for Islet Allograft Rejection

Saini

Ramachandran

Angaswamy

et al. 2008

American Journal of Transplantation

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T-cell activation up-regulates CD30 resulting in an increase in serum soluble CD30 (sCD30). CD4+ T cells, a major source for sCD30, play a significant role in the pathogenesis of rejection. In this study, sCD30 was measured pre-and posttransplant in mouse islet allograft models and human islet allograft recipients. sCD30 was measured by ELISA in diabetic C57BL/6, CD4Knockout (KO) and CD8KO islet allograft recipients. sCD30 increased significantly prior to rejection (1.8 ± 1 days) in 80% of allograft recipients. Sensitization with donor splenocytes, or a second graft, further increased sCD30 (282.5 ± 53.5 for the rejecting first graft vs. 374.6 ± 129 for the rejecting second graft) prior to rejection suggesting memory CD4+ T cells contribute to sCD30. CD4KO failed to reject islet allograft and did not demonstrate sCD30 increase. CD8KO showed elevated (227 ± 107) sCD30 (1 day) prior to rejection. High pretransplant sCD30 (>20 U/ml) correlated with poor outcome in human islet allograft recipients. Further, increase in sCD30 posttransplant preceded (3-4 months) loss of islet function. We conclude that sCD30 is released from activated CD4 T cells prior to islet allograft rejection and monitoring sCD30 can be a valuable adjunct in the follow-up of islet transplant recipients.

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CD4+25+ Regulatory T Cells Limit Th1-Autoimmunity by Inducing IL-10 Producing T Cells Following Human Lung Transplantation

Abstract: Chronic human lung allograft rejection is manifested by bronchiolitis obliterans syndrome (BOS).

Cited by 91 publications

References 57 publications

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

De Novo Production of K-α1 Tubulin-Specific Antibodies: Role in Chronic Lung Allograft Rejection

Activated Effector and Memory T Cells Contribute to Circulating sCD30: Potential Marker for Islet Allograft Rejection

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