Dissecting the Multiplicity of Immune Effects of Immunosuppressive Drugs to Better Predict the Risk of de novo Malignancies in Solid Organ Transplant Patients

Cangemi, Michela; Montico, Barbara; Faè, Damiana Antonia; Steffan, Agostino; Dolcetti, Riccardo

doi:10.3389/fonc.2019.00160

Cited by 29 publications

(21 citation statements)

References 196 publications

(209 reference statements)

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“…Review Article on Strategies to Achieve Long-Term Success of Lung Transplantation have been associated with increased risk of cancer after solid organ transplantation (SOT) (5). In the setting of impaired cell-mediated immunity, oncogenic viruses such as Epstein-Barr virus (EBV), human papilloma virus (HPV) and others have emerged as major risk factors for cancer development (4,6). Various immunosuppressive agents/regimens may also directly impact cancer risk that is independent of their effects on the overall level of immunosuppression.…”

Section: Induction Agents That Deplete T-lymphocytes In Particularmentioning

confidence: 99%

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Malignancy after lung transplantation

Shtraichman¹,

Ahya²

2020

Ann Transl Med

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Lung transplantation is an established therapeutic option for selected patients with advanced lung diseases. As early outcomes after lung transplantation have improved, chronic medical illnesses have emerged as significant obstacles to long-term survival. Among them is post-transplant malignancy, currently representing the 2 nd most common cause of death 5-10 years after transplantation. Chronic immunosuppressive therapy and resulting impairment of anti-tumor immune surveillance is thought to have a central role in cancer development after solid organ transplantation (SOT). Lung transplant recipients receive more immunosuppression than other SOT populations, likely contributing to even higher risk of cancer among this group. The most common cancers in lung transplant recipients are non-melanoma skin cancers, followed by lung cancer and post-transplant lymphoproliferative disorder (PTLD). The purpose of this review is to outline the common malignancies following lung transplant, their risk factors, prognosis and current means for both prevention and treatment.

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Section: Induction Agents That Deplete T-lymphocytes In Particularmentioning

confidence: 99%

“…The necessary requirement for post-transplant chronic immunosuppressive therapy and resulting impairment of anti-tumor immune surveillance and anti-viral activity is thought to have a central role in cancer development (4).…”

Section: Introductionmentioning

confidence: 99%

Malignancy after lung transplantation

Shtraichman¹,

Ahya²

2020

Ann Transl Med

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“…Many animal models and in vitro studies describe IST effects, but few studies detail effects of in vivo chronic posttransplant IST exposure on human PBMC 3,32,46,50,54,55,72‐75 57–64 …”

Section: Discussionmentioning

confidence: 99%

“…However, pharmacologic IST utilization is accompanied by substantial rates of cardiovascular and renal damage, diabetes, infection, and therapy-related malignancies as well as socioeconomic costs of chronic medication dependence. [1][2][3][4][5][6] Graft survival remains a problem. 4,7 Therefore, alternatives producing similarly low rates of acute and/or chronic graft rejection while minimizing toxicities of chronic pharmacologic IST are desirable.…”

Section: Introductionmentioning

confidence: 99%

Ex vivo generation of regulatory T cells from liver transplant recipients using costimulation blockade

Shimozawa

Contreras-Ruiz

Sousa

et al. 2022

American Journal of Transplantation

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The potential of adoptive cell therapy with regulatory T cells (Tregs) to promote transplant tolerance is under active exploration. However, the impact of specific transplant settings and protocols on Treg manufacturing is not well‐delineated. Here, we compared the use of peripheral blood mononuclear cells (PBMCs) from patients before or after liver transplantation to the use of healthy control PBMCs to determine their suitability for Treg manufacture using ex vivo costimulatory blockade with belatacept. Despite liver failure or immunosuppressive therapy, the capacity for Treg expansion during the manufacturing process was preserved. These experiments did not identify performance or quality issues that disqualified the use of posttransplant PBMCs—the currently favored protocol design. However, as Treg input correlated with output, significant CD4‐lymphopenia in both pre‐ and posttransplant patients limited Treg yield. We therefore turned to leukapheresis posttransplant to improve absolute yield. To make deceased donor use feasible, we also developed protocols to substitute splenocytes for PBMCs as allostimulators. In addition to demonstrating that this Treg expansion strategy works in a liver transplant context, this preclinical study illustrates how characterizing cellular input populations and their performance can both inform and respond to clinical trial design and Treg manufacturing requirements.

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“…Two of the most commonly and effectively used immunosuppressive drugs used after organ transplantation are rapamycin (Rapa) and cyclosporine A (CsA) (Enderby and Keller 2015;Moini et al 2015). For many years, their main targets were thought to be T cells; however, it has recently been found that immunosuppressive agents could also inhibit DC maturation and allostimulatory capacity (Cangemi et al 2019;Macedo et al 2012). Not only has this provided a new insight into the immunopharmacology of these substances, but it also offers novel strategies for the manipulation of DCs ex vivo prior to organ transplantation to promote tolerance induction.…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine A, in Contrast to Rapamycin, Affects the Ability of Dendritic Cells to Induce Immune Tolerance Mechanisms

Machcińska

Kotur

Jankowska

et al. 2021

Arch. Immunol. Ther. Exp.

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Following organ transplantation, it is essential that immune tolerance is induced in the graft recipient to reduce the risk of rejection and avoid complications associated with the long-term use of immunosuppressive drugs. Immature dendritic cells (DCs) are considered to promote transplant tolerance and may minimize the risk of graft rejection. The aim of the study was to evaluate the effects of immunosuppressive agents: rapamycin (Rapa) and cyclosporine A (CsA) on generation of human tolerogenic DCs (tolDCs) and also to evaluate the ability of these cells to induce mechanisms of immune tolerance. tolDCs were generated in the environment of Rapa or CsA. Next, we evaluated the effects of these agents on surface phenotypes (CD11c, MHC II, CD40, CD80, CD83, CD86, CCR7, TLR2, TLR4), cytokine production (IL-4, IL-6, IL-10, IL-12p70, TGF-β), phagocytic capacity and resistant to lipopolysaccharide activation of these DCs. Moreover, we assessed ability of such tolDCs to induce T cell activation and apoptosis, Treg differentiation and production of Th1- and Th2-characteristic cytokine profile. Data obtained in this study demonstrate that rapamycin is effective at generating maturation-resistant tolDCs, however, does not change the ability of these cells to induce mechanisms of immune tolerance. In contrast, CsA affects the ability of these cells to induce mechanisms of immune tolerance, but is not efficient at generating maturation-resistant tolDCs.

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Dissecting the Multiplicity of Immune Effects of Immunosuppressive Drugs to Better Predict the Risk of de novo Malignancies in Solid Organ Transplant Patients

Cited by 29 publications

References 196 publications

Malignancy after lung transplantation

Malignancy after lung transplantation

Ex vivo generation of regulatory T cells from liver transplant recipients using costimulation blockade

Cyclosporine A, in Contrast to Rapamycin, Affects the Ability of Dendritic Cells to Induce Immune Tolerance Mechanisms

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