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Ex Vivo Generation ...
Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade
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- Watanabe, M. (author)
- Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden;Karolinska Univ Hosp, Dept Transplantat Surg, Huddinge, Sweden
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- Kumagai-Braesch, Makiko (author)
- Karolinska Institutet
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- Yao, M. (author)
- Karolinska Institutet
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- Thunberg, S. (author)
- Karolinska Univ Hosp, Dept Clin Immunol, Stockholm, Sweden
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- Berglund, David, 1984- (author)
- Uppsala universitet,Klinisk immunologi
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- Sellberg, Felix (author)
- Uppsala universitet,Klinisk immunologi
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- Jorns, C. (author)
- Karolinska Institutet
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- Enoksson, S. Lind (author)
- Karolinska Institutet
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- Henriksson, J. (author)
- Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden;Karolinska Univ Hosp, Dept Transplantat Surg, Huddinge, Sweden
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- Lundgren, T. (author)
- Karolinska Institutet
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- Uhlin, M. (author)
- Karolinska Institutet
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- Berglund, E. (author)
- Karolinska Institutet
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- Ericzon, B-G (author)
- Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden;Karolinska Univ Hosp, Dept Transplantat Surg, Huddinge, Sweden
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(creator_code:org_t)
- 2018-09-27
- 2018
- English.
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In: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 27:11, s. 1692-1704
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Abstract
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- Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 x 10(6) cells) with irradiated donor PBMCs (20 x 10(6) cells) from eight human leukocyte antigen-mismatched responder-donor pairs in the presence of either 2D10.4/IT2.2 (3 mu g/10(6) cells) or belatacept (40 mu g/10(6) cells). After 14 days of coculture, the frequencies of CD4(+) T cells, CD8(+) T cells, and natural killer cells as well as interferon gamma (IFN-gamma) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19(+) B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4(+)CD25(+)CD127(low)FOXP3(+) T cells increased from 4.1 +/- 1.0% (preculture) to 7.1 +/- 2.6% and 7.3 +/- 2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p<0.05). Concurrently, delta-2 FOXP3 mRNA expression increased significantly. Compared with cells derived from the no-antibody treated control group, cells generated from both the 2D10.4/IT2.2- and belatacept-treated groups produced lower IFN-gamma and higher interleukin-10 levels in response to donor-antigens, as detected by enzyme-linked immunospot. Most importantly, 2D10.4/IT2.2- and belatacept-generated cells effectively impeded the proliferative responses of freshly isolated responder PBMCs against donor-antigens. Our results indicate that belatacept-generated donor-specific immunomodulatory cells possess comparable phenotypes and immunomodulatory efficacies to those generated with 2D10.4/IT2.2. We suggest that belatacept could be used for ex vivo generation of clinical grade alloantigen-specific immunomodulatory cells for tolerance induction after transplantation.
Subject headings
- NATURVETENSKAP -- Biologi -- Immunologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Immunology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Keyword
- Immunomodulatory cells
- anti-CD80/86 antibodies
- CTLA4-Ig
- donor antigen specificity
- ex vivo generation
- FOXP3
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Watanabe, M.
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Kumagai-Braesch, ...
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Yao, M.
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Thunberg, S.
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Berglund, David, ...
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Sellberg, Felix
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show more...
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Jorns, C.
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Enoksson, S. Lin ...
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Henriksson, J.
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Lundgren, T.
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Uhlin, M.
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Berglund, E.
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Ericzon, B-G
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Immunology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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Cell Transplanta ...
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Uppsala University
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Karolinska Institutet