B Cell Immunity in Lung Transplant Rejection - Effector Mechanisms and Therapeutic Implications

Ohm, Birte; Jungraithmayr, Wolfgang

doi:10.3389/fimmu.2022.845867

Cited by 12 publications

(8 citation statements)

References 126 publications

(148 reference statements)

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“…Due to the fact that B cells have multiple functions, including immunoglobulin production, cytokine production, and antigen presentation, therapeutic approaches targeting B-cells are important for controlling AMR [35,36]. Smirnova et al identified the infiltration of grafts by activated B cells in a mouse model of chronic rejection, showing that B cells are deeply involved in chronic rejection [37].…”

Section: Discussionmentioning

confidence: 99%

Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation

Matsumoto,

Suzuki,

Yamanaka

et al. 2023

Life

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Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in addition to calcineurin inhibitors in preventing AMR. Thus, this study aimed to evaluate the efficacy of aCD20 treatment in a murine orthotopic lung transplantation model. Murine left lung transplantation was performed using a major alloantigen strain mismatch model (BALBc (H-2d) → C57BL/6 (BL/6) (H-2b)). There were four groups: isograft (BL/6→BL/6) (Iso control), no-medication (Allo control), cyclosporine A (CyA) treated, and CyA plus murine aCD20 (CyA+aCD20) treated groups. Severe neutrophil capillaritis, arteritis, and positive lung C4d staining were observed in the allograft model and CyA-only-treated groups. These findings were significantly improved in the CyA+aCD20 group compared with those in the Allo control and CyA groups. The B cell population in the spleen, lymph node, and graft lung as well as the levels of serum donor-specific IgM and interferon γ were significantly lower in the CyA+aCD20 group than in the CyA group. Calcineurin inhibitor-mediated immunosuppression combined with aCD20 therapy effectively suppressed AMR in lung transplantation by reducing donor-specific antibodies and complement activation.

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Section: Discussionmentioning

confidence: 99%

Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation

Matsumoto,

Suzuki,

Yamanaka

et al. 2023

Life

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“…The exact relationship of eosinophil counts and allograft rejection is not fully understood and many investigators are still trying to dissect the complex interaction of key mediators in transplant alloimmunity [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. For several years, we have considered eosinophils as an epiphenomenon highly correlating with lung allograft rejection, which is supported by recent research [ 18 ].…”

Section: Why Consider Eosinophils and Lymphocytes?mentioning

confidence: 99%

Adaptive Immunosuppression in Lung Transplant Recipients Applying Complementary Biomarkers: The Zurich Protocol

et al. 2023

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Achieving adequate immunosuppression for lung transplant recipients in the first year after lung transplantation is a key challenge. Prophylaxis of allograft rejection must be balanced with the adverse events associated with immunosuppressive drugs, for example infection, renal failure, and diabetes. A triple immunosuppressive combination is standard, including a steroid, a calcineurin inhibitor, and an antiproliferative compound beginning with the highest levels of immunosuppression and a subsequent tapering of the dose, usually guided by therapeutic drug monitoring and considering clinical results, bronchoscopy sampling results, and additional biomarkers such as serum viral replication or donor-specific antibodies. Balancing the net immunosuppression level required to prevent rejection without overly increasing the risk of infection and other complications during the tapering phase is not well standardized and requires repeated assessments for dose-adjustments. In our adaptive immunosuppression approach, we additionally consider results from the white blood cell counts, in particular lymphocytes and eosinophils, as biomarkers for monitoring the level of immunosuppression and additionally use them as therapeutic targets to fine-tune the immunosuppressive strategy over time. The concept and its rationale are outlined, and areas of future research mentioned.

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“…The final effect is to stop the activation of lymphocyte cells, which generates immunosuppression. In vivo, rapamycin has a direct effect on immune-mediated responses to suppress T- and B-cell activation, such as allograft rejection [ 67 ]. Rapamycin, on the other hand, does not directly block mTOR kinase activity.…”

Section: Mtor Inhibitors: Chemistry and Mechanistic Perspectives On C...mentioning

confidence: 99%

Recent advances and limitations of mTOR inhibitors in the treatment of cancer

et al. 2022

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The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.

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B Cell Immunity in Lung Transplant Rejection - Effector Mechanisms and Therapeutic Implications

Cited by 12 publications

References 126 publications

Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation

Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation

Adaptive Immunosuppression in Lung Transplant Recipients Applying Complementary Biomarkers: The Zurich Protocol

Recent advances and limitations of mTOR inhibitors in the treatment of cancer

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