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. 2011 Jun;30(6):624-31.
doi: 10.1016/j.healun.2011.01.708. Epub 2011 Mar 16.

Alloimmunity-induced autoimmunity as a potential mechanism in the pathogenesis of chronic rejection of human lung allografts

Deepti Saini  1 , Joseph Weber, Sabarinathan Ramachandran, Donna Phelan, Venkataswarup Tiriveedhi, Michael Liu, Nancy Steward, Aviva Aloush, Ramsey Hachem, Elbert Trulock, Bryan Meyers, G Alexander Patterson, Thalachallour Mohanakumar
Affiliations

Alloimmunity-induced autoimmunity as a potential mechanism in the pathogenesis of chronic rejection of human lung allografts

Deepti Saini et al. J Heart Lung Transplant. 2011 Jun.

Abstract

Background: Bronchiolitis obliterans syndrome (BOS) is a major cause of morbidity and mortality after lung transplantation (LTx). We sought to better understand the relationship between alloimmune responses and autoimmunity and, subsequently, how autoimmunity leads to chronic rejection.

Methods: We analyzed the development of donor-specific antibodies (Abs) in LTx by flow PRA and the development of Abs to K-α1 tubulin (K-α1T) and collagen V (ColV) by ELISA. The frequency of K-α1T- and ColV-specific T cells that secrete IFN-γ, IL-17 and IL-10 in LTx recipients was measured by ELISPOT.

Results: In a retrospective analysis of 42 LTx recipients, we demonstrated a strong correlation between development of donor-specific anti-HLA Abs, Abs to self-antigens and BOS (p < 0.05). To test the hypothesis that alloimmunity is related to an immune response to self-antigens, we analyzed 103 LTx patients prospectively for the development of donor-specific Abs (DSA) and Abs to self-antigens. A total of 42.7% of recipients developed DSA and 30.1% developed Abs to K-α1T and ColV. Development of DSA preceded development of Abs to self-antigens. BOS(+) patients had higher frequency of T cells secreting IL-17 (p < 0.01) and IFN-γ (p < 0.05) with decreased IL-10 (p < 0.05) when compared with BOS(-) patients.

Conclusions: Based on these results we propose that alloimmune responses to donor HLA can induce autoimmune responses to airway epithelial self-antigens, characterized by activation of the IL-17 pathway. These immune responses to self-antigens along with alloimmunity contribute to the pathogenesis of BOS. Strategies to prevent development of autoimmunity may be play a key role in preventing the development of chronic rejection.

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Figures

Figure 1
Figure 1
A. Elevated levels of K-α1T Abs in serum of BOS+ patients compared to BOS− patients. Sera from 20 BOS+ patients and 22 BOS− patients and 12 normal volunteers were analyzed by ELISA for anti-K-α1T Abs as described in materials and methods section. BOS+ patients have higher levels of Abs to K-α1T in comparison to BOS− patients (p<0.05) and control (p<0.01). B. Elevated levels of K-α1T Abs in BAL of BOS+ patients compared to BOS− patients. BAL from 20 BOS+ patients and 22 BOS− patients were analyzed by ELISA for anti-K-α1T Abs. BOS+ patients have higher levels of Abs to K-α1T in comparison to BOS− patients (p<0.05) C. Elevated levels of ColV Abs in BOS+ patients compared to BOS− patients. Sera from 12 BOS+ patients, 12 BOS− patients and 8 normal volunteers were analyzed by ELISA for Abs to ColV as described in materials and methods. Patients with BOS have significantly higher levels of Abs to ColV compared to BOS– patients (p<0.05) as well as controls (p<0.01)
Figure 2
Figure 2. Persistence of Auto-Abs in the serum of LTx patients though anti-HLA Abs are not detected
Development of Anti-HLA Abs and Abs to K-α1T in the serum of four patients with respect to time is plotted. Anti-HLA Abs are shown in dotted lines and anti-K-α1T Abs as bars. Values above the cutoff line are considered positive. These results demonstrate that Abs to mismatched donor HLA (DSA) appear prior to the development of Abs to self-antigens. DSA appears transiently during the post-transplant period. Abs to self-antigens, once developed, persists even in the absence of detectable DSA.
Figure 3A
Figure 3A. Higher proliferation in BOS+ LTx patients after PBMCs are stimulated with K-α1T/ColV
After stimulation with 5μg/ml K-α1T/ColV PBMCs from BOS+ patients were tested for proliferation against these self-antigens by Thymidine incorporation and compared to BOS− patients (n=10 in each group). PBMCs from all BOS+ patients demonstrated significantly higher proliferation to K-α1T compared to BOS− patients (>2 folds, p<0.01).
Figure 3B
Figure 3B. Decreased IL-10 and higher IFN-γ production against K-α1T in BOS+ LTx patients
PBMCs from BOS+ and BOS− patients (n=10 in each group) were stimulated with 5μg/ml K-α1T, followed by detection of IL-10 and IFN-γ production by ELISPOT. BOS+ patients showed significantly decreased production of IL-10 (64.8 vs. 212 spm, p<0.05) and increased IFN-γ (234.6 vs. 165 spm, p<0.05) secreting cells against K-α1T.
Figure 3C
Figure 3C. Higher frequency of IL-17 producing cells in BOS+ LTx patients against K-α1T
PBMCs isolated from BOS+ and BOS− patients (n=10 in each group) were stimulated with 5μg/ml K-α1T or ColV, followed by detection of IL-17 production by ELISPOT. BOS+ patients showed significantly higher IL-17 producing cells against K-α1T (176 vs. 63 spm, p<0.01) compared to BOS− patients. ColV stimulated BOS+ cells also produce higher IL-17 compared to BOS− cells (120 vs. 50 spm, p<0.05)
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