Preoperative mucosal tolerance to brain antigens and a neuroprotective immune response following surgical brain injury

Laboratory investigation

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Object

Intracranial surgery causes cortical injury from incisions, hemorrhage, retraction, and electrocautery. The term “surgical brain injury” (SBI) has been developed to categorize this injury inherent to the procedure. Neuroinflammation plays a significant role in SBI. Traditional antiinflammatory therapies are often limited by their immunosuppressive side effects and poor CNS penetration. This study uses mucosal tolerance to develop an immune system that is tolerant to brain myelin basic protein (MBP) so that inflammation can be suppressed in a timely and site-specific manner following surgical disruption of the blood-brain barrier.

Methods

A standard SBI model using CD57 mice was used. Nasopharyngeal mucosa was exposed to vehicle, ovalbumin, or MBP to develop mucosal tolerance to these antigens. Immunological tolerance to MBP was confirmed in vivo through hypersensitivity testing. Neurological scores, cerebral edema, and interleukin (IL)–1β and transforming growth factor (TGF)–β1 cytokine levels were measured 48 hours postoperatively.

Results

Hypersensitivity testing confirmed the development of immune tolerance to MBP. Myelin basic protein–tolerant mice demonstrated reduced neurological injury, less cerebral edema, decreased levels of IL-1β, and increased levels of TGFβ1 following SBI.

Conclusions

Developing preoperative immunological tolerance to brain antigens through mucosal tolerance provides neuroprotection, reduces brain edema, and modulates neuroinflammation following SBI.

Abbreviations used in this paper: BBB = blood-brain barrier; IL = interleukin; MBP = myelin basic protein; PBS = phosphate-buffered saline; SBI = surgical brain injury; TGF = transforming growth factor.

Article Information

Address correspondence to: John H. Zhang, M.D., Ph.D., Department of Neurosurgery, Loma Linda University Medical Center, 11234 Anderson Street, Room 2562B, Loma Linda, California 92354. email: johnzhang3910@yahoo.com.

Please include this information when citing this paper: published online October 21, 2011; DOI: 10.3171/2011.8.JNS11883.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graph of hypersensitivity to MBP. Measurement of footpad thickness shows that MBP-tolerant mice developed a much smaller inflammatory reaction, than PBS- or ovalbumin (OVA)–treated mice, when MBP was injected subcutaneously into the footpad following MBP immunization. The Holm-Sidak test for pairwise comparisons was performed and the p values were less than the critical levels indicated in the figure (statistically significant). Six mice per group. Error bars represent the SEM.

  • View in gallery

    Graph comparing postoperative neurological scores among 6 groups of mice (12 mice per group except SBI + OVA and SBI + MBP [14 mice per group]). Surgical brain injury resulted in significant loss of neurological function 24 and 48 hours after surgery. The MBP-tolerant groups show a significant preservation of neurological function 24 and 48 hours after SBI. The Holm-Sidak test for pairwise comparisons was performed and the p values were less than the critical levels indicated in the figure (statistically significant).

  • View in gallery

    Graph comparing brain water content 48 hours after SBI among 6 groups of mice (6 mice per group for all groups except SBI + OVA and SBI + MBP [8 mice per group]). Brain water content was unchanged among treatments in the sham groups. Surgical brain injury caused significant increases in brain water content among all treatment groups. The postoperative increase in brain water content was significantly reduced in MBP-tolerant mice compared with vehicle (PBS) and ovalbumin groups. The Holm-Sidak test for pairwise comparisons was performed and the p values were less than the critical levels indicated in the figure (statistically significant).

  • View in gallery

    Graph showing the effects of mucosal tolerance on cerebral cytokine levels following SBI among 6 groups of mice (6 mice per group). Left: Levels of IL-1β were equal among all sham groups. Levels were significantly increased in the SBI + PBS and SBI + OVA groups. The MBP-tolerant mice did not demonstrate an increase in IL-1β after SBI. Levels of IL-1β were significantly higher in the SBI + PBS and SBI + OVA groups compared with the SBI + MBP group. Right: Levels of TGFβ1 were equal among all sham groups. Levels of TGFβ1 were reduced by approximately 50% in the SBI + PBS and SBI + OVA groups. There was no reduction in TGFβ1 in MBP-tolerant mice after SBI. Post-SBI levels of TGFβ1 were significantly higher in the MBP-tolerant mice than in the SBI + PBS or SBI + OVA groups. Expression levels of each protein using Western blots are expressed as a ratio of β-actin levels for normalization. The Holm-Sidak test for pairwise comparisons was performed and the p values were less than the critical levels indicated in the figure (statistically significant).

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