Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
EJNMMI Research
Published in: EJNMMI Research 1/2015

Open Access 01-12-2015 | Original research

Non-invasive molecular imaging of inflammatory macrophages in allograft rejection

Authors: Alexander S. G. O’Neill, Samantha Y. A. Terry, Kathryn Brown, Lucy Meader, Andrew M. S. Wong, Jonathan D. Cooper, Paul R. Crocker, Wilson Wong, Gregory E. D. Mullen

Published in: EJNMMI Research | Issue 1/2015

Login to get access

Abstract

Background

Macrophages represent a critical cell type in host defense, development and homeostasis. The ability to image non-invasively pro-inflammatory macrophage infiltrate into a transplanted organ may provide an additional tool for the monitoring of the immune response of the recipient against the donor graft. We therefore decided to image in vivo sialoadhesin (Sn, Siglec 1 or CD169) using anti-Sn mAb (SER-4) directly radiolabelled with 99mTc pertechnetate.

Methods

We used a heterotopic heart transplantation model where allogeneic or syngeneic heart grafts were transplanted into the abdomen of recipients. In vivo nanosingle-photon emission computed tomography (SPECT/CT) imaging was performed 7 days post transplantation followed by biodistribution and histology.

Results

In wild-type mice, the majority of 99mTc-SER-4 monoclonal antibody cleared from the blood with a half-life of 167 min and was located predominantly on Sn+ tissues in the spleen, liver and bone marrow. The biodistribution in the transplantation experiments confirmed data derived from the non-invasive SPECT/CT images, with significantly higher levels of 99mTc-SER-4 observed in allogeneic grafts (9.4 (±2.7) %ID/g) compared to syngeneic grafts (4.3 (±10.3) %ID/g) (p = 0.0022) or in mice which received allogeneic grafts injected with 99mTc-IgG isotype control (5.9 (±0.6) %ID/g) (p = 0.0185). The transplanted heart to blood ratio was also significantly higher in recipients with allogeneic grafts receiving 99mTc-SER-4 as compared to recipients with syngeneic grafts (p = 0.000004) or recipients with allogeneic grafts receiving 99mTc-IgG isotype (p = 0.000002).

Conclusions

Here, we demonstrate that imaging of Sn+ macrophages in inflammation may provide an important additional and non-invasive tool for the monitoring of the pathophysiology of cellular immunity in a transplant model.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol. 2005;23:901–44.CrossRefPubMed
4.
Zola H, Swart B, Nicholson I, Voss E. Leukocyte and stromal cell molecules: the CD markers. Hoboken: Wiley-Liss; 2007.
5.
Beckmann N, Cannet C, Babin AL, Ble FX, Zurbruegg S, Kneuer R, et al. In vivo visualization of macrophage infiltration and activity in inflammation using magnetic resonance imaging. Rev Nanomed Nanobiotechnol. 2009;1:272–98.CrossRef
6.
Berry DJ, Ma Y, Ballinger JR, Tavare R, Koers A, Sunassee K, et al. Efficient bifunctional gallium-68 chelators for positron emission tomography: tris(hydroxypyridinone) ligands. Chem Commun. 2011;47:7068–70.CrossRef
7.
Van Hemert FJ, Voermans C, Van Eck-Smit BL, Bennink RJ. Labeling monocytes for imaging chronic inflammation. J Nucl Med Mol Imaging. 2009;53:78–88.
8.
Terry SY, Boerman OC, Gerrits D, Franssen GM, Metselaar JM, Lehmann S, et al. 111In-anti-F4/80-A3-1 antibody: a novel tracer to image macrophages. Eur J Nucl Med Mol Imaging. 2015;42:1430–8.PubMedCentralCrossRefPubMed
9.
Eichendorff S, Svendsen P, Bender D, Keiding S, Christensen EI, Deleuran B, et al. Biodistribution and PET imaging of a novel [68Ga]-anti-CD163-antibody conjugate in rats with collagen-induced arthritis and in controls. Mol Imaging Biol. 2015;17:87–93.CrossRefPubMed
10.
Sun X, Gao D, Gao L, Zhang C, Yu X, Jia B, et al. Molecular imaging of tumor-infiltrating macrophages in a preclinical mouse model of breast cancer. Theranostics. 2015;5:597–608.PubMedCentralCrossRefPubMed
11.
Boutin H, Murray K, Pradillo J, Maroy R, Smigova A, Gerhard A, et al. 18 F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke. Eur J Nucl Med Mol Imaging. 2015;42:503–11.CrossRefPubMed
12.
Crocker PR, Gordon S. Mouse macrophage hemagglutinin (sheep erythrocyte receptor) with specificity for sialylated glycoconjugates characterized by a monoclonal antibody. J Exp Med. 1989;169:1333–46.CrossRefPubMed
13.
Klaas M, Crocker PR. Sialoadhesin in recognition of self and non-self. Semin Immunopathol. 2012;34:353–64.CrossRefPubMed
14.
O'Neill AS, van den Berg TK, Mullen GE. Sialoadhesin—a macrophage-restricted marker of immunoregulation and inflammation. Immunology. 2013;138:198–207.PubMedCentralCrossRefPubMed
15.
Hartnell A, Steel J, Turley H, Jones M, Jackson DG, Crocker PR. Characterization of human sialoadhesin, a sialic acid binding receptor expressed by resident and inflammatory macrophage populations. Blood. 2001;97:288–96.CrossRefPubMed
16.
Ikezumi Y, Suzuki T, Hayafuji S, Okubo S, Nikolic-Paterson DJ, Kawachi H, et al. The sialoadhesin (CD169) expressing a macrophage subset in human proliferative glomerulonephritis. Nephrol Dial Transplant. 2005;20:2704–13.CrossRefPubMed
17.
Nath D, Hartnell A, Happerfield L, Miles DW, Burchell J, Taylor-Papadimitriou J, et al. Macrophage-tumour cell interactions: identification of MUC1 on breast cancer cells as a potential counter-receptor for the macrophage-restricted receptor, sialoadhesin. Immunology. 1999;98:213–9.PubMedCentralCrossRefPubMed
18.
Martinez-Pomares L, Gordon S. CD169+ macrophages at the crossroads of antigen presentation. Trends Immunol. 2012;33:66–70.CrossRefPubMed
19.
Asano K, Nabeyama A, Miyake Y, Qiu CH, Kurita A, Tomura M, et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity. 2011;34:85–95.CrossRefPubMed
20.
Phan TG, Green JA, Gray EE, Xu Y, Cyster JG. Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation. Nat Immunol. 2009;10:786–93.PubMedCentralCrossRefPubMed
21.
Barral P, Polzella P, Bruckbauer A, van Rooijen N, Besra GS, Cerundolo V, et al. CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nat Immunol. 2010;11:303–12.PubMedCentralCrossRefPubMed
22.
Backer R, Schwandt T, Greuter M, Oosting M, Jungerkes F, Tuting T, et al. Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells. Proc Natl Acad Sci U S A. 2010;107:216–21.PubMedCentralCrossRefPubMed
23.
Poderoso T, Martinez P, Alvarez B, Handler A, Moreno S, Alonso F, et al. Delivery of antigen to sialoadhesin or CD163 improves the specific immune response in pigs. Vaccine. 2011;29:4813–20.CrossRefPubMed
24.
Ip CW, Kroner A, Crocker PR, Nave KA, Martini R. Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice. Neurobiol Dis. 2007;25:105–11.CrossRefPubMed
25.
Kobsar I, Oetke C, Kroner A, Wessig C, Crocker P, Martini R. Attenuated demyelination in the absence of the macrophage-restricted adhesion molecule sialoadhesin (Siglec-1) in mice heterozygously deficient in P0. Mol Cell Neurosci. 2006;31:685–91.CrossRefPubMed
26.
Wu C, Rauch U, Korpos E, Song J, Loser K, Crocker PR, et al. Sialoadhesin-positive macrophages bind regulatory T cells, negatively controlling their expansion and autoimmune disease progression. J Immunol. 2009;182:6508–16.PubMedCentralCrossRefPubMed
27.
Xiong YS, Zhou YH, Rong GH, Wu WL, Liang Y, Yang ZX, et al. Siglec-1 on monocytes is a potential risk marker for monitoring disease severity in coronary artery disease. Clin Biochem. 2009;42:1057–63.CrossRefPubMed
28.
Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342:605–12.CrossRefPubMed
29.
Badar A, DeFreitas S, McDonnell JM, Yahya N, Thakor D, Razavi R, et al. Recombinant complement receptor 2 radiolabeled with [99mTc(CO)3]+: a potential new radiopharmaceutical for imaging activated complement. PLoS One. 2011;6, e18275.PubMedCentralCrossRefPubMed
30.
Corry RJ, Winn HJ, Russell PS. Heart transplantation in congenic strains of mice. Transplant Proc. 1973;5:733–5.PubMed
31.
Hnatowich DJ, Mardirossian G, Rusckowski M, Fogarasi M, Virzi F, Winnard Jr P. Directly and indirectly technetium-99 m-labeled antibodies—a comparison of in vitro and animal in vivo properties. J Nucl Med. 1993;34:109–19.PubMed
32.
Sykes TR, Woo TK, Baum RP, Qi P, Noujaim AA. Direct labeling of monoclonal antibodies with technetium-99 m by photoactivation. J Nucl Med. 1995;36:1913–22.PubMed
33.
Malviya G, Galli F, Sonni I, Pacilio M, Signore A. Targeting T and B lymphocytes with radiolabelled antibodies for diagnostic and therapeutic applications. J Nucl Med Mol Imaging. 2010;54:654–76.
34.
Goldsmith SJ, Signore A. An overview of the diagnostic and therapeutic use of monoclonal antibodies in medicine. J Nucl Med Mol Imaging. 2010;54:574–81.
35.
van den Berg TK, van Die I, de Lavalette CR, Dopp EA, Smit LD, van der Meide PH, et al. Regulation of sialoadhesin expression on rat macrophages. Induction by glucocorticoids and enhancement by IFN-beta, IFN-gamma, IL-4, and lipopolysaccharide. J Immunol. 1996;157:3130–8.PubMed
36.
Delputte PL, Van Breedam W, Delrue I, Oetke C, Crocker PR, Nauwynck HJ. Porcine arterivirus attachment to the macrophage-specific receptor sialoadhesin is dependent on the sialic acid-binding activity of the N-terminal immunoglobulin domain of sialoadhesin. J Virol. 2007;81:9546–50.PubMedCentralCrossRefPubMed
37.
38.
Salehi S, Reed EF. The divergent roles of macrophages in solid organ transplantation. Curr Opin Organ Transplant. 2015;20:446–53.CrossRefPubMed
39.
40.
Kimura A, Naka T, Kishimoto T. IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci U S A. 2007;104:12099–104.PubMedCentralCrossRefPubMed
41.
Pilmore HL, Painter DM, Bishop GA, McCaughan GW, Eris JM. Early up-regulation of macrophages and myofibroblasts: a new marker for development of chronic renal allograft rejection. Transplantation. 2000;69:2658–62.CrossRefPubMed
42.
Ashokkumar C, Gabriellan A, Ningappa M, Mazariegos G, Sun Q, Sindhi R. Increased monocyte expression of sialoadhesin during acute cellular rejection and other enteritides after intestine transplantation in children. Transplantation. 2012;93:561–4.CrossRefPubMed
Metadata
Title
Non-invasive molecular imaging of inflammatory macrophages in allograft rejection
Authors
Alexander S. G. O’Neill
Samantha Y. A. Terry
Kathryn Brown
Lucy Meader
Andrew M. S. Wong
Jonathan D. Cooper
Paul R. Crocker
Wilson Wong
Gregory E. D. Mullen
Publication date
01-12-2015
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2015
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-015-0146-7

Other articles of this Issue 1/2015

EJNMMI Research 1/2015 Go to the issue

Original research

Evaluation of elastix-based propagated align algorithm for VOI- and voxel-based analysis of longitudinal 18F-FDG PET/CT data from patients with non-small cell lung cancer (NSCLC)

Preliminary research

Rapid kit-based 68Ga-labelling and PET imaging with THP-Tyr3-octreotate: a preliminary comparison with DOTA-Tyr3-octreotate

Original research

Role of CD8-positive cells in radioimmunotherapy utilizing 177Lu-mAbs in an immunocompetent rat colon carcinoma model

Original research

Twins in spirit - episode I: comparative preclinical evaluation of [68Ga]DOTATATE and [68Ga]HA-DOTATATE

Original research

Novel 89Zr cell labeling approach for PET-based cell trafficking studies

Original research

Gene expression signature in mouse thyroid tissue after 131I and 211At exposure