Critical Role of Proinflammatory Cytokine IL-6 in Allograft Rejection and Tolerance
Open accessAbstract
The proinflammatory cytokine IL-6 plays an important role in controlling T-cell differentiation, especially the development of Th17 and regulatory T cells. To determine the function of IL-6 in regulating allograft rejection and tolerance, BALB/c cardiac grafts were transplanted into wild-type or IL-6-deficient C57BL/6 mice. We observed that production of IL-6 and IFN-γ was upregulated during allograft rejection in untreated wild-type mice. In IL-6-deficient mice, IFN-γ production was greater than that observed in wild-type controls, suggesting that IL-6 production affects Th1/Th2 balance during allograft rejection. CD28-B7 blockade by CTLA4-Ig inhibited IFN-γ production in C57BL/6 recipients, but had no effect on the production of IL-6. Although wild-type C57BL/6 recipients treated with CTLA4-Ig rejected fully MHC-mismatched BALB/c heart transplants, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft acceptance. Allograft acceptance appeared to result from the combined effect of costimulatory molecule blockade and IL-6-deficiency, which limited the differentiation of effector cells and promoted the migration of regulatory T cells into the grafts. These data suggest that the blockade of IL-6, or its signaling pathway, when combined with strategies that inhibit Th1 responses, has a synergistic effect on the promotion of allograft acceptance. Thus, targeting the effects of IL-6 production may represent an important part of costimulation blockade-based strategies to promote allograft acceptance and tolerance.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IFN-γ has been shown to promote allograft tolerance in certain settings by counteracting the effects of IL-5 and IL-6.
“IFN-γ has been shown to promote allograft tolerance in certain settings by counteracting the effects of both IL-5 and IL-6, which are strong mediators of allograft rejection, as previously published and also observed in our case26,32–36.”
From Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation (2019) · cites this paper as [34]
Cites
Hirano, T., Yasukawa, K., Harada, H., Taga, T., Watanabe, Y., Matsuda, T., Kashiwamura, S.-I., Nakajima, K., Koyama, K., Iwamatsu, A., et al. (1986) · Nature · doi:10.1038/324073a0 · Cited by 2,139 · see citing works
IL-17 family cytokines and the expanding diversity of effector T cell lineages
Weaver, C. T., Hatton, R. D., Mangan, P. R., & Harrington, L. E. (2007) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141557 · Cited by 1,842 · see citing works
Acquisition of lymphokine-producing phenotype by CD4+ T cells
Seder, R. A., & Paul, W. E. (1994) · Annual Review of Immunology · doi:10.1146/annurev.iy.12.040194.003223 · Cited by 1,557 · see citing works
Steinman, L. (2007) · Nature Medicine · doi:10.1038/nm1551 · Cited by 1,367 · see citing works
Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells
Rincón, M., Anguita, J., Nakamura, T., Fikrig, E., & Flavell, R. A. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.3.461 · Cited by 810 · see citing works
IL-6 signal transduction and its physiological roles: the signal orchestration model
Kamimura, D., Ishihara, K., & Hirano, T. (2003) · Reviews of Physiology, Biochemistry and Pharmacology · doi:10.1007/s10254-003-0012-2 · Cited by 673 · see citing works
The effects of IL-6 on CD4 T cell responses
Dienz, O., & Rincón, M. (2008) · Clinical Immunology · doi:10.1016/j.clim.2008.08.018 · Cited by 529 · see citing works
B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes.
Lotz, M., Jirik, F. R., Kabouridis, P. S., Tsoukas, C. D., Hirano, T., Kishimoto, T., & Carson, D. A. (1988) · The Journal of Experimental Medicine · doi:10.1084/jem.167.3.1253 · Cited by 526 · see citing works
A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy
Yuan, X., Paez-Cortez, J. R., Schmitt-Knosalla, I., D’Addio, F., Mfarrej, B. G., Donnarumma, M., Habicht, A., Clarkson, M. R., Iacomini, J., Glimcher, L. H., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20081937 · Cited by 302 · see citing works
Self-citationIL-6 rescues resting mouse T cells from apoptosis.
Teague, T., Marrack, P., Kappler, J., & Vella, A. (1997) · Journal of Immunology · doi:10.4049/jimmunol.158.12.5791 · Cited by 280 · see citing works
CTLA4Ig: Bridging the Basic Immunology with Clinical Application
Bluestone, J. A., Clair, E. W. S., & Turka, L. A. (2006) · Immunity · doi:10.1016/j.immuni.2006.03.001 · Cited by 276 · see citing works
Self-citationCutting Edge: Soluble IL-6R Is Produced by IL-6R Ectodomain Shedding in Activated CD4 T Cells
Briso, E. M., Dienz, O., & Rincón, M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7102 · Cited by 165 · see citing works
Piccotti, J. R., Chan, S. Y., VanBuskirk, A. M., EICHWALD, E. J., & Bishop, D. K. (1997) · Transplantation · doi:10.1097/00007890-199703150-00001 · Cited by 165 · see citing works
The Role of Helper T Cell Subsets in Autoimmune Diseases
Lafaille, J. J. (1998) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(98)00009-4 · Cited by 161 · see citing works
IL-6 Increases Primed Cell Expansion and Survival
Rochman, I., Paul, W., & Ben-Sasson, S. (2005) · Journal of Immunology · doi:10.4049/jimmunol.174.8.4761 · Cited by 138 · see citing works
Kishimoto, H., & Sprent, J. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.4.1817 · Cited by 108 · see citing works
IL-6 and TNF-α Synergistically Inhibit Allograft Acceptance
Shen, H., & Goldstein, D. R. (2009) · Journal of the American Society of Nephrology · doi:10.1681/asn.2008070778 · Cited by 94 · see citing works
Ayroldi, E., Zollo, O., Cannarile, L., Adamio, F. D., Grohmann, U., Delfino, D., & Riccardi, C. (1998) · Blood · doi:10.1182/blood.v92.11.4212 · Cited by 87 · see citing works
Prevention of type 1 diabetes by gene therapy
Tian, C., Bagley, J., Cretin, N., Seth, N. P., Wucherpfennig, K. W., & Iacomini, J. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22103 · Cited by 86 · see citing works
Self-citationLiang, Y., Christopher, K. B., Finn, P. W., Colson, Y. L., & Perkins, D. L. (2007) · Transplantation · doi:10.1097/01.tp.0000281384.24333.0b · Cited by 80 · see citing works
Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells
Yuan, X., Ansari, M. J., D’Addio, F., Paez-Cortez, J. R., Schmitt, I., Donnarumma, M., Boenisch, O., Zhao, X., Popoola, J., Clarkson, M. R., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812538106 · Cited by 63 · see citing works
Self-citationFinally, CTLA4Ig graduates to the clinic
Sayegh, M. H. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6952 · Cited by 61 · see citing works
Self-citationSteroid administration in heart and heart—lung transplantation: Is the timing adequate?
Wan, S., DeSmet, J.-M., Antoine, M., et al. (1996) · The Annals of Thoracic Surgery · doi:10.1016/0003-4975(95)01059-9 · Cited by 56 · see citing works
The Interleukin-12 Family: New Players in Transplantation Immunity?
Goriely, S., & Goldman, M. (2007) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2006.01651.x · Cited by 52 · see citing works
The inflammatory Th 17 subset in immunity against self and non-self antigens
Jin, D., Zhang, L., Zheng, J., & Zhao, Y. L. (2008) · Autoimmunity · doi:10.1080/08916930701776605 · Cited by 39 · see citing works
T-Cell Subsets: The More the Merrier
Weaver, C. T., & Murphy, K. M. (2007) · Current Biology · doi:10.1016/j.cub.2006.12.015 · Cited by 34 · see citing works
Increasing urinary IL-6 levels announce kidney graft rejection
Kaden, J., & Priesterjahn, R. (2000) · Transplant International · doi:10.1007/s001470050271 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Dare, A. J., Logan, A., Prime, T. A., Rogatti, S., Goddard, M., Bolton, E. M., Bradley, J. A., Pettigrew, G. J., Murphy, M. P., & Saeb-Parsy, K. (2015) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2015.05.007 · Cited by 119 · see citing works
Esfahani, K., Al-Aubodah, T.-A., Thebault, P., Lapointe, R., Hudson, M., Johnson, N. A., Baran, D., Bhulaiga, N., Takano, T., Cailhier, J.-F., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12628-1 · Cited by 109 · see citing works
- Authors
- Zhao, X., Boenisch, O., Yeung, M., Mfarrej, B., Yang, S., Turka, L. A., Sayegh, M. H., Iacomini, J., & Yuan, X.
- Affiliations
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Iacomini, J.
- Yuan, X.
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 12
- Issue
- 1
- Pages
- 90-101
- ISSN
- 1600-6135 (ISSN-L)
- OpenAlex
- W1496397714
- Cited by
- 104
- References
- 27
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 11 · 2018: 4 · 2017: 7 · 2016: 5 · 2015: 10 · 2014: 5 · 2013: 6 · 2012: 6
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI051559, P01-AI41521, R01-AI37691, R01AI037691, P01AI041521, R01AI070601, R01AI043619)
- Topics
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Transplantation › Organ and Tissue Transplantation Research
- Keywords
- interleukin-6, allograft rejection, allograft tolerance, heart transplantation, abatacept, costimulation blockade, interferon-gamma, Th1/Th2 balance, regulatory T cells, Th17 cells, T cell differentiation, MHC mismatch, IL-6 deficiency, graft acceptance
- MeSH terms
- Adaptation, Physiological, Animals, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Graft Rejection, Lymphocyte Culture Test, Mixed, Mice, Inbred BALB C, Mice, Inbred C57BL, CD4-Positive T-Lymphocytes, Interleukin-6, Heart Transplantation, CD8-Positive T-Lymphocytes, Inflammation Mediators, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
