Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Aug 15;187(4):1537-41.
doi: 10.4049/jimmunol.1100660. Epub 2011 Jul 18.

Cutting edge: A monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models

Dallas B Flies  1 , Shengdian Wang, Haiying Xu, Lieping Chen
Affiliations

Cutting edge: A monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models

Dallas B Flies et al. J Immunol. .

Abstract

Upon interaction with B7 homolog 1, programmed death-1 (PD-1) transmits a critical coinhibitory signal to T cells to negatively regulate immune responses. By extensively searching the genomic database with the IgV region of PD-1, we identified a homolog and named it PD-1 homolog (PD-1H). PD-1H is broadly expressed on the cell surface of hematopoietic cells and could be further upregulated on CD4(+) and CD8(+) T cells following activation. We have generated an mAb against PD-1H, which strikingly prevents acute graft-versus-host disease in semi- and fully allogeneic murine models, leading to full chimerism following treatment. Graft-versus-host disease remains a primary hindrance to successful allogeneic hematopoietic cell transplantation therapy for the treatment of hematologic malignancy. Therefore, manipulation of PD-1H function may provide a new modality for controlling T cell responses to allogeneic tissues in transplant medicine.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Genomic organization, sequence, and alignment of PD-1H. a) Mouse PD-1H is composed of seven exons: 5′ untranslated region (UTR) and signal peptide are located in exons 1 and 2; extracelluar domain is located in exons 2, 3, and 4; transmembrane domain is in exon 4; intracellular domain is in exons 4, 5, 6, and 7; 3′ UTR is located in exon 7. b) The mouse (top) and human full length PD-1H sequences have 85.6 % similarity (shaded). All seven cysteines are conserved between species (yellow). Mouse and human have three conserved N-linked glycosylation sites. Mouse PD-1H has four N-linked myristoylation sites (blue letters) while human PD-1H has only three. The mouse intracellular region has three tyrosine residues (blue), while the third tyrosine residue in the human protein is mutated to a histidine (red). Mouse and human proteins have two potential conserved PKC docking sites (red letters). Additionally, mouse and human PD-1H proteins have 15 conserved proline residues (green). c) Phylogenetic analysis of full length mouse PD-1H with CD28 family members using a Gonnet similarity matrix and neighbor joining method. d) Matrix of mouse PD-1H IgV domain identity (white) and identity+similarity (shaded) with members of the CD28 family IgV and IgC domains. e) Alignment of mouse PD-1H IgV domain with CD28 family member IgV and IgC domains. Similar and identical residues are shaded gray. Conserved cysteines required for IgV beta sheet linkage are in yellow (note BTLA has an IgC domain). Residues which align only for CD28, CTLA-4, and ICOS are in green, while residues which align for PD-1H and PD-1 are in blue. Ligand binding sites for BTLA, CD28, CTLA-4, and ICOS are in red blocks, while the PD-1 ligand binding site is in red letters.
FIGURE 2
FIGURE 2
PD-1H expression analysis. a) PD-1H mRNA is broadly expressed by multiple tissue blot. b) PD-1H mRNA is expressed in naïve and activated T cells, 6 day unstimulated and IFN-γ stimulated BMDCs, and PMA activated B cells. c) MH5A mAb binds P815 cells stably transfected with full-length mouse PD-1H, but not control transfected P185 cells (shaded histogram). Binding of MH5A was competitively inhibited by addition of excess soluble PD-1HIg. d) Expression of PD-1H on normal tissues by IHC examination of paraffin embedded C57BL/6 tissues using biotin labeled MH5A mAb. e) Flow cytometric analysis of PD-1H surface expression. Mouse F4/80+ peritoneal macrophages, circulating CD11+Gr-1+ neutrophils, and mature 7day GM-CSF+IL-4 cultured BM derived DCs are positive for PD-1H, as are a large percentage of total bone marrow cells. NK cells express low levels of PD-1H, while B cells are negative for PD-1H protein expression. Isotype control staining is shaded. Naïve CD4+ and CD8+ T cells constitutively express PD-1H (light shaded), which could be up further up-regulated within 2 hours when stimulated with PMA+ionomycin (open histogram). Isotype control for T cell staining is dark shaded.
FIGURE 3
FIGURE 3
Anti-PD-1H treatment robustly inhibits aGVHD. a) Lethally irradiated BDF1 mice received 5 × 106 TCD-BM + 3 × 106 pan T cells and 200 ug of hamIg (open triangles) or MH5A (closed squares) on day 0. inset) Analysis of chimerism at 30day by FACS analysis of circulating donor (H-2d negative) neutrophils (light gray), CD4+ T cells (dark gray) and CD8+ T cells (black bar). b) Lethally irradiated B6 mice received 5 × 106 BM + 1 × 107 total LN cells and 200μg hamIg (open triangles) or MH5A (closed squares) on day 0. inset) Analysis of chimerism at 30day for circulating donor (H-2d positive) neutrophils (light gray), CD4+ T cells (dark gray), and CD8+ T cells (black bar).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Wang S, Chen L. T lymphocyte co-signaling pathways of the B7-CD28 family. Cell. Mol. Immunol. 2004;1:37–42. - PubMed
    1. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu. Rev. Immunol. 2005;23:515–548. - PubMed
    1. Linsley PS, Clark EA, Ledbetter JA. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc. Natl. Acad. Sci. U. S. A. 1990;87:5031–5035. - PMC - PubMed
    1. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 1991;174:561–569. - PMC - PubMed
    1. Wang S, Zhu G, Chapoval AI, Dong H, Tamada K, Ni J, Chen L. Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood. 2000;96:2808–2813. - PubMed

Publication types

MeSH terms

Substances