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

Richards, David M.; Dalheimer, Stacy L.; Hertz, Marshall I.; Mueller, Daniel L.

doi:10.4049/jimmunol.171.12.6919

Cited by 26 publications

(33 citation statements)

References 32 publications

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“…Although large numbers of T cells could be recovered from mHAg-only disparate male grafts after transplantation into B6 female hosts, similar to BALB/c fully mismatched tracheas, there was a difference in the relative contributions of the CD4 ϩ and CD8 ϩ cells to the response. As previously reported (27,28), CD8 ϩ T cells were the dominant T cell observed to infiltrate BALB/c allografts ( Fig. 2A).…”

Section: Minor Hag-reactive Cd4supporting

confidence: 53%

“…Perhaps consistent with this, CD8-deficient B6 female mice transplanted with male bm1 tracheas can be shown to demonstrate a reduced potential to develop allograft luminal fibrosis (28). Nevertheless, it was formally possible that for the case of the chronic airway rejection seen in these experiments, CD8…”

Section: Minor Hag-reactive Cd4mentioning

confidence: 81%

“…Animals were transplanted as previously described (25,27,28). Briefly, donor mice were euthanized and skin-prepped with 70% ethanol (Sigma-Aldrich).…”

Section: Trachea Graftingmentioning

confidence: 99%

“…In previous experiments direct class I alloreactivity by CD8 ϩ T cells was shown to be an important stimulus for the development of OAD (27,28). Therefore, we hypothesized that male mHAginduced OAD often failed to occur because of the lack of a direct class I MHC target for CD8 ϩ T cells within the tracheal allografts.…”

Section: Minor Hag-reactive Cd4mentioning

confidence: 99%

“…This heterotopic tracheal transplantation system was originally developed by Hertz et al (25) as a mouse model of chronic lung transplant rejection (15,(25)(26)(27)(28). Animals were transplanted as previously described (25,27,28).…”

Section: Trachea Graftingmentioning

confidence: 99%

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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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Section: Minor Hag-reactive Cd4supporting

confidence: 53%

Section: Minor Hag-reactive Cd4mentioning

confidence: 81%

“…Animals were transplanted as previously described (25,27,28). Briefly, donor mice were euthanized and skin-prepped with 70% ethanol (Sigma-Aldrich).…”

Section: Trachea Graftingmentioning

confidence: 99%

Section: Minor Hag-reactive Cd4mentioning

confidence: 99%

Section: Trachea Graftingmentioning

confidence: 99%

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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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Partial decellularization eliminates immunogenicity in tracheal allografts

Tan

Liu

Dharmadhikari

et al. 2023

Bioengineering & Transla Med

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There is currently no suitable autologous tissue to bridge large tracheal defects. As a result, no standard of care exists for long‐segment tracheal reconstruction. Tissue engineering has the potential to create a scaffold from allografts or xenografts that can support neotissue regeneration identical to the native trachea. Recent advances in tissue engineering have led to the idea of partial decellularization that allows for the creation of tracheal scaffolds that supports tracheal epithelial formation while preserving mechanical properties. However, the ability of partial decellularization to eliminate graft immunogenicity remains unknown, and understanding the immunogenic properties of partially decellularized tracheal grafts (PDTG) is a critical step toward clinical translation. Here, we determined that tracheal allograft immunogenicity results in epithelial cell sloughing and replacement with dysplastic columnar epithelium and that partial decellularization creates grafts that are able to support an epithelium without histologic signs of rejection. Moreover, allograft implantation elicits CD8+ T‐cell infiltration, a mediator of rejection, while PDTG did not. Hence, we establish that partial decellularization eliminates allograft immunogenicity while creating a scaffold for implantation that can support spatially appropriate airway regeneration.

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Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus Recipient Immune System in a Murine Model of Bronchiolitis Obliterans

Schütte‐Nütgen

Boenisch

Harrach

et al. 2017

The American Journal of Pathology

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Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1-deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8 effector T cells. The function of PD-L1 on T cells after unspecific stimulation was dependent on both cell type and strength of stimulation. This novel function of recipient PD-L1 may result from the high degree of T-cell activation within the highly immunogenic milieu of the transplanted tissue. In this model, both decreased T-cell alloimmune responses and the reduction of BO in PD-L1-deficient recipients suggest a potential therapeutic role of selectively blocking PD-L1 in the recipient. Further investigation is warranted to determine the impact of this finding embedded in the complex pathophysiological context of BO.

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

Cited by 26 publications

References 32 publications

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

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

Partial decellularization eliminates immunogenicity in tracheal allografts

Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus Recipient Immune System in a Murine Model of Bronchiolitis Obliterans

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