Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance

Miller, Michelle L.; McIntosh, Christine; Williams, Jason; Wang, Ying; Hollinger, Maile K.; Isaad, Noel J.; Moon, James; Gajewski, Thomas F.; Chong, Anita S.; Alegre, Maria‐Luisa

doi:10.1016/j.celrep.2018.07.067

Cited by 18 publications

(24 citation statements)

References 58 publications

(72 reference statements)

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“…Since eosinophils accumulate in the allograft early after engraftment (7), they affect allorecognition at early time points and may alter the frequency of alloreactive T cell clones for the life of the graft. By interfering with the strength of TCR signal transduction, eosinophil-mediated downregulation of immune responses may mirror CSB shaping of the T cell repertoire toward lower-affinity clones (38). It is thus possible that such early action may indirectly affect long-term immunologic graft survival.…”

Section: Discussionmentioning

confidence: 99%

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

et al. 2019

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It has been demonstrated by us as well as others that eosinophils may alter their phenotype and function based on the local environment (7, 9, 10). Since costimulation plays a critical role in T cell cytokine production and environmental polarization (11, 12), we examined the possibility that eosinophils may lose their tolerogenic properties in the absence of CSB immunosuppression. Cytokine expression was examined in BALB/c (H2 d) lung allografts transplanted into fully MHC-mismatched C57BL/6 (B6) (H2 b) recipient mice. In the absence of immunosuppression, lung allografts had higher levels of Th1-polarizing cytokines IFN-γ and TNF-α than did CSB-treated accepting lung grafts (Figure 1A). Limited amounts of Th2-polarizing cytokines IL-4, IL-13, IL-33, and GM-CSF were evident in lung allografts treated with or without CSB immunosuppression (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.128241DS1). We next evaluated lung-resident eosinophils from both CSB-treated and nonimmunosuppressed grafts. Based on a previously identified eosinophil polarization phenotype (7), we noted higher levels of Th1-defining (or E1-defining) features, such as CXCL9, CXCL10, CXCL11, and iNOS in eosinophils isolated from rejecting compared with CSB-treated lung allografts (Figure 1A). In no group was Th2 (or E2) polarization of eosinophils detected (Supplemental Figure 1A). Flow cytometric characterization demonstrated an absence of MHC II and costimulatory molecules such as CD80, CD86, and CD40. However, there were high levels of recipient-derived MHC I (H2K b), PD-L1, and CD101 on lung-resident eosinophils in the absence of CSB (Figure 1B). Notably, we did not detect BALB/c-derived H2 d-MHC on graft-resident eosinophils, indicating a lack of "cross-dressing" or antigen swapping for donor derived-antigens (ref. 13 and Supplemental Figure 1B). Thus, while eosinophils from rejecting lungs resembled those from accepting lungs in some aspects, we did observe some differences. It is thus possible that in the absence of immunosuppression, eosinophils may contribute to graft rejection rather than acceptance, specifically because CD101 expression has been previously associated with an inflammatory eosinophil subtype (14). In order to evaluate this directly, we conditionally depleted eosinophils from B6 iPHIL mice, in which the diphtheria toxin (DT) receptor is expressed under the control of the eosinophil peroxidase promoter (Supplemental Figure 1C and ref. 15). DT-treated mice or saline-injected controls were challenged with a BALB/c lung allograft in the absence of immunosuppression. Surprisingly, mice depleted of eosinophils had higher grades of rejection (Figure 1C), increased numbers of lung-resident T lymphocytes, increased rates of T cell proliferation, and increased effector cell differentiation by day 4 after engraftment (Figure 1D). These patterns of T lymphocyte activation and infiltration were especially prominent for CD8 + T cells. CD4 + T cell proliferation did ...

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Section: Discussionmentioning

confidence: 99%

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

et al. 2019

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“…Finally, despite comparable levels of CD40 expression by AdTr tolerant and naive B cells (Supplemental Figure 4, D and E), reduced DSA production by tolerant B cells was observed in MD4 mice treated with agonistic anti-CD40 antibody plus CpG at doses capable of preventing anti-CD154/DSC-induced tolerance (21) and of stimulating polyclonal B cell activation ( Figure 3G and Supplemental Figure 5). Thus, tolerant B cells transferred into naive with K d -specific B cells (19).…”

Section: Resultsmentioning

confidence: 94%

Transplantation tolerance modifies donor-specific B cell fate to suppress de novo alloreactive B cells

Khiew

Jain

Chen

et al. 2020

Journal of Clinical Investigation

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“…This may well reflect lower-avidity peptide binding by these responsive cells, compared to the tetramerpositive cells, which is nevertheless physiologically relevant. Indeed, the respective roles of high-and low-avidity TCR binding interactions are of interest in studies of multiple allo-immune responses including allograft rejection and vaccine efficacy (103)(104)(105). As mentioned earlier, both antibody phenotyping and analysis of secreted cytokines have confirmed the involvement of both Th1 and Th2 subsets of CD4 + T-effectors in inhibitor development.…”

Section: Cd4 + T-cell Response To Fviiimentioning

confidence: 90%

Tolerating Factor VIII: Recent Progress

et al. 2020

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Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ∼30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

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Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance

Cited by 18 publications

References 58 publications

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

Transplantation tolerance modifies donor-specific B cell fate to suppress de novo alloreactive B cells

Tolerating Factor VIII: Recent Progress

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