Biologics in organ transplantation

Page, Eugenia K.; Dar, Wasim; Knechtle, Stuart J.

doi:10.1111/j.1432-2277.2012.01456.x

Cited by 28 publications

(15 citation statements)

References 170 publications

(166 reference statements)

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“…10 Yet, polyclonal antithymocyte globulins target multiple cell populations including lymphocytes, natural killer (NK) cells, monocytes, macrophages and DCs. 9,10 In addition, monoclonal biologics such as anti-CD52 antibody alemtuzumab do not target one specific cell type but a conglomerate of cells including T cells, B cells, NK cells, macrophages, DCs and eosinophils. 11 Application of those biologics is therefore associated with sustained immunosuppression and an inherent risk of infectious disease.…”

Section: Introductionmentioning

confidence: 99%

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Blank

Welker

Haarer

et al. 2014

Bone Marrow Transplant

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Allograft rejection and immunosuppression are two major issues in transplantation medicine. The specific targeting of alloreactive T cells, the initiators and promoters of allograft rejection, would be a promising strategy to reduce unwanted T-cell responses and side effects of lifelong immunosuppression. The novel humanized monoclonal antibody GZ-αβTCR, specific for the human αβT-cell receptor, was tested in vitro and in vivo for its specificity and efficacy to modulate the αβT-cell compartment. GZ-αβTCR moderately induced apoptosis in resting αβT cells in vitro, an effect considerably amplified in activated T cells. A single dose of GZ-αβTCR significantly reduced human CD45 + CD3 + T cells in vivo, with a preferential modulation of CD4 + αβT cells. Importantly, naive T cells, the T-cell subset from which alloreactivity emanates, were significantly reduced. Simultaneously, a significant, compensatory increase of γδ T cells was observed in vitro and in vivo in both humanized mouse models examined. GZ-αβTCR did not induce cytokines and was well tolerated. Thus, specificity and high efficacy make GZ-αβTCR a powerful tool to selectively eliminate putatively detrimental T-cell subsets, a major goal in transplantation medicine. At the same time, GZ-αβTCR spares γδ and natural killer cells, thus leaving the recipient's immune system competent for cell-mediated immunoregulation and cell-mediated immunity.

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Section: Introductionmentioning

confidence: 99%

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Blank

Welker

Haarer

et al. 2014

Bone Marrow Transplant

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“…Statistical significance was indicated as follows: approaches, including mAbs. 4,36,37 The understanding of how TNFSF and TNFRSF molecules contribute to the development of the immune response in different models of disease is essential for translation of the research findings into clinical practice. As members of the TNF/TNFRSF family control the absolute number of effector T cells and modulate the speed of the T cell differentiation process, they dictate the frequency of memory T cells that subsequently develop into long-lived memory T cells.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells

Rio

Fernández-Renedo

Chaloin

et al. 2016

mAbs

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(2016) Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells, mAbs, 8:3, 478-490, DOI: 10.1080/19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 ABSTRACTTumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C-terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFSFR14) and the lymphotoxin b receptor (LTbR, TNFSFR3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graftversus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LTbR/HVEM pathway was associated with delayed downregulation of interleukin-7Ra and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LTbR/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival.Abbreviations: LIGHT, homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T

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“…This reflects a particular scenario of clinical interventions such as, for example, immunosuppressive regimens based on thymoglobulin or anti-CD52 antibody therapy (alemtuzumab) with depleting activity on lymphoid cells. 27,28 …”

Section: Resultsmentioning

confidence: 99%

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation

Rodríguez-Barbosa

Ferreras

Bühler

et al. 2018

mAbs

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Natural killer (NK) cells are a population of innate type I lymphoid cells essential for early anti-viral responses and are known to modulate the course of humoral and cellular-mediated T cell responses. We assessed the role of NK cells in allogeneic CD8 T cell-mediated responses in an immunocompetent mouse model across an MHC class I histocompatibility barrier to determine its impact in therapeutic clinical interventions with polyclonal or monoclonal antibodies (mAbs) targeting lymphoid cells in transplantation. The administration of an NK cell depleting antibody to either CD8 T cell replete or CD8 T cell-depleted naïve C57BL/6 immunocompetent mice accelerated graft rejection. This accelerated rejection response was associated with an in vivo increased cytotoxic activity of CD8 T cells against bm1 allogeneic hematopoietic cells and bm1 skin allografts. These findings show that NK cells were implicated in the control host anti-donor cytotoxic responses, likely by competing for common cell growth factors in both CD8 T cell replete and CD8 T cell-depleted mice, the latter reconstituting in response to lymphopenia. Our data calls for precaution in solid organ transplantation under tolerogenic protocols involving extensive depletion of lymphocytes. These pharmacological biologics with depleting properties over NK cells may accelerate graft rejection and promote aggressive CD8 T cell cytotoxic alloresponses refractory to current immunosuppression.

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Biologics in organ transplantation

Cited by 28 publications

References 170 publications

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation

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