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The free radical scavenger S-PBN significantly prolongs DSG-mediated graft survival in experimental xenotransplantation

Biglarnia, Ali-Reza ; Emanuelsson, Cecilia LU orcid ; Quach, My ; Clausen, Fredrik LU ; Larsson, Erik ; Schneider, Mårten K J ; Tufveson, Gunnar and Lorant, Tomas (2012) In Xenotransplantation 19(3). p.76-166
Abstract

BACKGROUND: Nitrones such as 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) are known to trap and stabilize free radicals and to reduce inflammation. Recently, S-PBN was shown to reduce infiltration of T lymphocytes and the expression of adhesion molecules on the endothelium in experimental traumatic brain injury. We hypothesized that S-PBN could reduce infiltration of T lymphocytes during cell-mediated xenograft rejection and thereby increase graft survival. The concordant mouse-to-rat heart transplantation model was used to test the hypothesis. In this model, grafts undergo acute humoral xenograft rejection (AHXR) almost invariably on day 3 and succumb to cell-mediated rejection on approximately day 8 if AHXR is inhibited by treatment... (More)

BACKGROUND: Nitrones such as 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) are known to trap and stabilize free radicals and to reduce inflammation. Recently, S-PBN was shown to reduce infiltration of T lymphocytes and the expression of adhesion molecules on the endothelium in experimental traumatic brain injury. We hypothesized that S-PBN could reduce infiltration of T lymphocytes during cell-mediated xenograft rejection and thereby increase graft survival. The concordant mouse-to-rat heart transplantation model was used to test the hypothesis. In this model, grafts undergo acute humoral xenograft rejection (AHXR) almost invariably on day 3 and succumb to cell-mediated rejection on approximately day 8 if AHXR is inhibited by treatment with 15-deoxyspergualin (DSG).

MATERIAL AND METHODS: Hearts from Naval Medical Research Institute (NMRI) mice were transplanted to the neck vessels of Lewis rats. Recipients were treated with S-PBN (n=9), DSG (n=9), S-PBN and DSG in combination (n=10) or left untreated (n=9) for survival studies. S-PBN was given daily intraperitoneally at a dose of 150 mg/kg body weight (BW) on day -1 to 30, and DSG was given daily intraperitoneally at a dose of 10 mg/kg BW on day -1 to 4 and 5 mg/kg BW on day 5 to 21. Nine additional recipients were given S-PBN only on days -1 and 0 in combination with continuous DSG treatment. Grafts were monitored until they stopped beating. Additional recipients were treated with S-PBN (n=5), DSG (n=5), S-PBN and DSG in combination (n=6) or left untreated (n=5) for morphological, immunohistochemical and flow cytometry analyses on days 2 and 6 after transplantation.

RESULTS: S-PBN treatment in combination with DSG resulted in increased median graft survival compared to DSG treatment alone (14 vs. 7 days; P=0.019). Lower number of T lymphocytes on day 6 (P=0.019) was observed by ex vivo propagation and flow cytometry when combining S-PBN with DSG, whereas immunohistochemical analyses demonstrated a significant reduction in the number of infiltrated CD4+, but not TCR+, cells. S-PBN treatment alone had no impact on graft survival compared to untreated rats (3 vs. 3 days). No differences were seen in ICAM-1 and VCAM-1 expression or in morphology between the groups.

CONCLUSION: The combination of S-PBN and DSG treatment increases xenograft survival. The main effect of S-PBN appears to be in direct connection with the transplantation. Because of its low toxicity, S-PBN could become useful in combination with other immunosuppressants to reduce cell-mediated xenograft rejection.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Animals, Outbred Strains, Benzenesulfonates/pharmacology, Drug Therapy, Combination, Free Radical Scavengers/pharmacology, Graft Rejection/immunology, Graft Survival/drug effects, Guanidines/pharmacology, Heart Transplantation/methods, Immunosuppressive Agents/pharmacology, Intercellular Adhesion Molecule-1/metabolism, Lymph Nodes/cytology, Lymphocyte Activation/immunology, Male, Mice, Rats, Rats, Inbred Lew, Spleen/cytology, T-Lymphocytes/immunology, Tissue and Organ Harvesting/methods, Transplantation, Heterologous/methods, Vascular Cell Adhesion Molecule-1/metabolism
in
Xenotransplantation
volume
19
issue
3
pages
11 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:84862580675
  • pmid:22702468
ISSN
0908-665X
DOI
10.1111/j.1399-3089.2012.00700.x
language
English
LU publication?
no
additional info
© 2012 John Wiley & Sons A/S.
id
d868a9e0-644a-487e-89fa-4d9857489ac4
date added to LUP
2025-12-17 14:18:42
date last changed
2025-12-18 04:02:08
@article{d868a9e0-644a-487e-89fa-4d9857489ac4,
  abstract     = {{<p>BACKGROUND: Nitrones such as 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) are known to trap and stabilize free radicals and to reduce inflammation. Recently, S-PBN was shown to reduce infiltration of T lymphocytes and the expression of adhesion molecules on the endothelium in experimental traumatic brain injury. We hypothesized that S-PBN could reduce infiltration of T lymphocytes during cell-mediated xenograft rejection and thereby increase graft survival. The concordant mouse-to-rat heart transplantation model was used to test the hypothesis. In this model, grafts undergo acute humoral xenograft rejection (AHXR) almost invariably on day 3 and succumb to cell-mediated rejection on approximately day 8 if AHXR is inhibited by treatment with 15-deoxyspergualin (DSG).</p><p>MATERIAL AND METHODS: Hearts from Naval Medical Research Institute (NMRI) mice were transplanted to the neck vessels of Lewis rats. Recipients were treated with S-PBN (n=9), DSG (n=9), S-PBN and DSG in combination (n=10) or left untreated (n=9) for survival studies. S-PBN was given daily intraperitoneally at a dose of 150 mg/kg body weight (BW) on day -1 to 30, and DSG was given daily intraperitoneally at a dose of 10 mg/kg BW on day -1 to 4 and 5 mg/kg BW on day 5 to 21. Nine additional recipients were given S-PBN only on days -1 and 0 in combination with continuous DSG treatment. Grafts were monitored until they stopped beating. Additional recipients were treated with S-PBN (n=5), DSG (n=5), S-PBN and DSG in combination (n=6) or left untreated (n=5) for morphological, immunohistochemical and flow cytometry analyses on days 2 and 6 after transplantation.</p><p>RESULTS: S-PBN treatment in combination with DSG resulted in increased median graft survival compared to DSG treatment alone (14 vs. 7 days; P=0.019). Lower number of T lymphocytes on day 6 (P=0.019) was observed by ex vivo propagation and flow cytometry when combining S-PBN with DSG, whereas immunohistochemical analyses demonstrated a significant reduction in the number of infiltrated CD4+, but not TCR+, cells. S-PBN treatment alone had no impact on graft survival compared to untreated rats (3 vs. 3 days). No differences were seen in ICAM-1 and VCAM-1 expression or in morphology between the groups.</p><p>CONCLUSION: The combination of S-PBN and DSG treatment increases xenograft survival. The main effect of S-PBN appears to be in direct connection with the transplantation. Because of its low toxicity, S-PBN could become useful in combination with other immunosuppressants to reduce cell-mediated xenograft rejection.</p>}},
  author       = {{Biglarnia, Ali-Reza and Emanuelsson, Cecilia and Quach, My and Clausen, Fredrik and Larsson, Erik and Schneider, Mårten K J and Tufveson, Gunnar and Lorant, Tomas}},
  issn         = {{0908-665X}},
  keywords     = {{Animals; Animals, Outbred Strains; Benzenesulfonates/pharmacology; Drug Therapy, Combination; Free Radical Scavengers/pharmacology; Graft Rejection/immunology; Graft Survival/drug effects; Guanidines/pharmacology; Heart Transplantation/methods; Immunosuppressive Agents/pharmacology; Intercellular Adhesion Molecule-1/metabolism; Lymph Nodes/cytology; Lymphocyte Activation/immunology; Male; Mice; Rats; Rats, Inbred Lew; Spleen/cytology; T-Lymphocytes/immunology; Tissue and Organ Harvesting/methods; Transplantation, Heterologous/methods; Vascular Cell Adhesion Molecule-1/metabolism}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{76--166}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Xenotransplantation}},
  title        = {{The free radical scavenger S-PBN significantly prolongs DSG-mediated graft survival in experimental xenotransplantation}},
  url          = {{http://dx.doi.org/10.1111/j.1399-3089.2012.00700.x}},
  doi          = {{10.1111/j.1399-3089.2012.00700.x}},
  volume       = {{19}},
  year         = {{2012}},
}