Mesenchymal Stromal Cell Infusions as Rescue Therapy for Corticosteroid-Refractory Adult Autoimmune Enteropathy

doi:10.1016/j.mayocp.2012.04.014

Mayo Clinic Proceedings

Volume 87, Issue 9, September 2012, Pages 909-914

https://doi.org/10.1016/j.mayocp.2012.04.014 Get rights and content

Abstract

Adult autoimmune enteropathy (AIE) is a rare cause of malabsorption syndrome unresponsive to dietary restriction. Its diagnostic hallmarks are small-bowel villous atrophy and antienterocyte autoantibodies. Therapy is based mainly on nutritional support and immunosuppression. We treated a 61-year-old woman with corticosteroid-refractory AIE and life-threatening malabsorption syndrome with systemic infusions of autologous, bone marrow–derived, mesenchymal stromal cells (MSCs) as rescue therapy. The MSCs were expanded ex vivo following a previously used Good Manufacturing Practice procedure, and 2 intravenous infusions of 1.8 × 10⁶ MSCs/kg body weight were administered 2 weeks apart. Analysis of circulating and mucosal regulatory T-and B-cell numbers, and of serum and secretory immunoglobulin levels, was performed before and after treatment. The MSC infusions were safe and effective, leading to disappearance of disease hallmarks and recovery from the life-threatening condition. Increases in mucosal regulatory T-cell numbers and secretory immunoglobulin levels were also observed. The benefit, however, was transient, and a further MSC infusion resulted in the same short efficacy. This case encourages the use of MSCs to treat patients with life-threatening, corticosteroid-refractory AIE and suggests that MSC infusion can attenuate, albeit transiently, the autoimmune attack.

Section snippets

Case Report

In March 2009, a 61-year-old woman was hospitalized for severe malabsorption syndrome due to chronic diarrhea lasting 2 years. Findings from stool examinations for occult blood and pathogens were negative; findings from lower endoscopy were unremarkable, whereas upper endoscopy with biopsy showed villous atrophy and inflammatory infiltrate of the duodenal mucosa. Although the results of serologic screening for celiac disease (the search for antiendomysium and anti–tissue transglutaminase

Patient Outcome

No adverse event was recorded during MSC infusion or in the following 22 months. A few days after the second infusion, the patient experienced a dramatic amelioration of her clinical condition and regularization of stool frequency, permitting her hospital discharge within 1 week. One month later, enterocyte autoantibodies were no longer detectable, and patchy recovery of duodenal mucosa at endoscopic and histologic examination was clearly evident (Figure 1, B), together with normalization of

Discussion

In the past decade, MSCs have been proposed and used as a new therapeutic strategy in immune-mediated disorders.¹³ Regarding chronic inflammatory bowel disease, we have already successfully treated fistulizing Crohn disease refractory to conventional treatments with local injections of autologous bone marrow–derived MSCs.¹⁴ After a benefit was observed in a mouse model of multiorgan autoimmunity,⁶ we used MSC infusions as described herein as rescue therapy in a patient with life-threatening

Conclusion

These data suggest that MSC infusions are safe and useful in the short term for treating AIE, mainly when refractory to current therapies. The increase in regulatory T-cell and plasma cell numbers in the gut mucosa may play a role in silencing the pathogenic pathways leading to autoantibody production and tissue injury. However, further in vivo studies are needed to explain the lack of long-lasting benefits and to define the optimal conditions for the use of MSCs as immunotherapy.

Acknowledgments

We thank Dr Paola Bianchi for detection of antienterocyte antibody, Dr Sergio Rutella for critical reading of the manuscript, and Mrs Susan West for careful revision of the English language.

References (20)

G.R. Corazza et al.
Autoimmune enteropathy and villous atrophy in adults
Lancet
(1997)
I. Kobayashi et al.
Identification of an autoimmune enteropathy-related 75-kilodalton antigen
Gastroenterology
(1999)
S. Akram et al.
Adult autoimmune enteropathy: Mayo Clinic Rochester experience
Clin Gastroenterol Hepatol
(2007)
K. Le Blanc et al.
Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study
Lancet
(2008)
J.D. Fontenot et al.
Regulatory T cell lineage specification by the forkhead transcription factor foxp3
Immunity
(2005)
F. Dazzi et al.
Mesenchymal stem cells and autoimmune diseases
Best Pract Res Clin Haematol
(2011)
A. Uccelli et al.
Why should mesenchymal stem cells (MSCs) cure autoimmune diseases?
Curr Opin Immunol
(2010)
A. Corcione et al.
Human mesenchymal stem cells modulate B-cell functions
Blood
(2006)
B. Fang et al.
Resolution of refractory chronic autoimmune thrombocytopenic purpura following mesenchymal stem cell transplantation: a case report
Transplant Proc
(2009)
M.E. Bernardo et al.
Mesenchymal stromal cells: a novel treatment modality for tissue repair
Ann N Y Acad Sci
(2009)

There are more references available in the full text version of this article.

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: Grant Support: This study was supported in part by grants from Fondazione Celiachia Italia (“Studio di possibili fattori ambientali e sviluppo di nuove strategie terapeutiche nelle complicanze della malattia celiaca”) (G.R.C); Ministero dell'Istruzione, dell'Università e della Ricerca, Progetti di Rilevante Interesse Nazionale; Associazione Italiana per la Ricerca sul Cancro; Ospedale Pediatrico Bambino Gesù, Roma; and the Associazione Italiana per la Ricerca sul Cancro special project “5 per mille” (F.L.).

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Case reportMesenchymal Stromal Cell Infusions as Rescue Therapy for Corticosteroid-Refractory Adult Autoimmune Enteropathy

Abstract

Section snippets

Case Report

Patient Outcome

Discussion

Conclusion

Acknowledgments

Lancet

Gastroenterology

Clin Gastroenterol Hepatol

Lancet

Immunity

Best Pract Res Clin Haematol

Curr Opin Immunol

Blood

Transplant Proc

Mesenchymal stromal cells: a novel treatment modality for tissue repair

Ann N Y Acad Sci

Case report
Mesenchymal Stromal Cell Infusions as Rescue Therapy for Corticosteroid-Refractory Adult Autoimmune Enteropathy