Skip to main content

Advertisement

SpringerLink
Log in

Autologous Human Cytomegalovirus-Specific Cytotoxic T Cells as Rescue Therapy for Ulcerative Enteritis in Primary Immunodeficiency

  • Brief Communication
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Purpose

Patients affected by primary immunodeficiency usually undergo a wide range of infections, including reactivation of latent ones. Here we report two cases suffering from late-onset combined immunodeficiency in which ulcerative enteritis due to human Cytomegalovirus caused a life-threatening malabsorption syndrome.

Methods

The assessment of the viral load was carried out on both blood and mucosal samples by quantitative real-time polymerase chain reaction assay. The generation of autologous virus-specific cytotoxic T cell lines was performed according to Good Manufacturing Practice protocol after peripheral blood mononuclear cells were collected through a single leukapheresis.

Results

In both patients, the viral load resulted negligible in peripheral blood, but very high in mucosal specimens (range 1.064 - 1.031.692 copies/105 cells). After two rounds of antiviral therapy proved unsuccessful, the generation of virus-specific cytotoxic T cell lines was carried out despite severe lymphopenia, and their infusion resulted safe and durably effective in healing intestinal ulcerations and resetting the viral load.

Conclusions

Virus-specific cellular therapy was useful in reconstituting specific immunity and treating severe human Cytomegalovirus-related enteritis in patients with primary immunodeficiency.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Abbreviations

CVID:

Common variable immunodeficiency

HCMV:

Human Cytomegalovirus

IPEX:

immunodysregulation, polyendocrinopathy, enteropathy, X-linked

TCLs:

T cell lines

FOXP3:

transcription factor forkhead box P3

References

  1. Griffiths PD. Burden of disease associated with human cytomegalovirus and prospects for elimination by universal immunization. Lancet Infect Dis. 2012;12:790–8.

    Article  PubMed  Google Scholar 

  2. Baroco AL, Oldfield EC. Gastrointestinal cytomegalovirus disease in the immunocompromised patient. Curr Gastroenterol Rep. 2008;10:409–16.

    Article  PubMed  Google Scholar 

  3. Halliday E, Winkelstein J, Webster AD. Enteroviral infections in primary immunodeficiency (PID): a survey of morbidity and mortality. J Infect. 2003;46:1–8.

    Article  CAS  PubMed  Google Scholar 

  4. Stack E, Washington K, Avant GR, Eisen GM. Cytomegalovirus enteritis in common variable immunodeficiency. South Med J. 2004;97:96–101.

    Article  PubMed  Google Scholar 

  5. Einsele H, Kapp M, Grigoleit GU. CMV-specific T cell therapy. Blood Cells Mol Dis. 2008;40:71–5.

    Article  CAS  PubMed  Google Scholar 

  6. Walter EA, Greenberg PD, Gilbert MJ, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995;333:1038–44.

    Article  CAS  PubMed  Google Scholar 

  7. Peggs KS, Verfuerth S, Pizzey A, et al. Cytomegalovirus-specific T cell immunotherapy promotes restoration of durable functional antiviral immunity following allogeneic stem cell transplantation. Clin Infect Dis. 2009;49:1851–60.

    Article  CAS  PubMed  Google Scholar 

  8. Comoli P, Labirio M, Basso S, et al. Infusion of autologous EBV-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood. 2002;99:2592–8.

    Article  CAS  PubMed  Google Scholar 

  9. Paquin-Proulx D, Santos BA, Carvalho KI, et al. IV Ig immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID. PLoS One. 2013;8:e75199.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002;39:537–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol. 2007;119:482–7.

    Article  CAS  PubMed  Google Scholar 

  12. Roifman CM, Somech R, Kavadas F, et al. Defining combined immunodeficiency. J Allergy Clin Immunol. 2012;130:177–83.

    Article  CAS  PubMed  Google Scholar 

  13. Malphettes M, Gérard L, Carmagnat M, et al. Late-onset combined immunodeficiency: a subset of common variable immunodeficiency with severe T cell defect. Clin Infect Dis. 2009;49:1329–38.

    Article  CAS  PubMed  Google Scholar 

  14. Furione M, Rognoni V, Cabano E, et al. Kinetics of human cytomegalovirus (HCMV) DNAemia in transplanted patients expressed in international units as determined with the Abbott RealTime CMV assay and an in-house assay. J Clin Virol. 2012;55:317–22.

    Article  CAS  PubMed  Google Scholar 

  15. Mayer A, Podlech J, Kurz S, et al. Bone marrow failure by cytomegalovirus is associated with an in vivo deficiency in the expression of essential stromal hemopoietin genes. J Virol. 1997;71:4589–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Malamut G, Verkarre V, Suarez F, et al. The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease. Am J Gastroenterol. 2010;105:2262–75.

    Article  CAS  PubMed  Google Scholar 

  17. Bendiksen S, Van Ghelue M, Rekvig OP, et al. A longitudinal study of human cytomegalovirus serology and viruria fails to detect active viral infection in 20 systemic lupus erythematous patients. Lupus. 2000;9:120–6.

    Article  CAS  PubMed  Google Scholar 

  18. Farrinfton M, Grosmaire LS, Nonoyama S, et al. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc Natl Acad Sci U S A. 1994;91:1099–103.

    Article  Google Scholar 

  19. Liston A, Enders A, Siggs OM. Unravelling the association of partial T-cell immunodeficiency and immune dysregulation. Nat Rev Immunol. 2008;8:545–58.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to acknowledge the support of the Technical Director (Dr. Rita Maccario) and the Quality Assessment Coordinator (Dr. Antonia Moretta) of the Cell Factory; they are also grateful to Dr. Elena Strada (Endoscopic Unit) who carried out the endoscopy examinations with appropriate biopsy sampling, and to Dr. Cesare Perotti (Immunotransfusion Service) who carried out the leukapheresis (all from the IRCCS Policlinico San Matteo Foundation, Pavia; Italy), to Drs. Eleonora Gambineri and Marina Vignoli (Department of Pediatrics, University of Florence; Italy) who carried out the genetic characterization, and to Ms. Sheila McVeigh for her thorough revision of the English text.

Funding

PC is the recipient of a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC), and from Ministero della Salute, Ricerca Finalizzata.

Conflict of Interest Disclosure

Rachele Ciccocioppo, Patrizia Comoli, Alessandra Gallia, Sabrina Basso, Fausto Baldanti, and Gino Roberto Corazza have no conflict of interest and financial disclosure to declare.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation - University of Pavia, Pavia, Italy

    Rachele Ciccocioppo, Alessandra Gallia & Gino Roberto Corazza

  2. Pediatric Hematology-Oncology Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy

    Patrizia Comoli & Sabrina Basso

  3. Molecular Virology Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy

    Fausto Baldanti

  4. Centre for the Study and Cure of Celiac Disease, Clinica Medica I, IRCCS Policlinico San Matteo Foundation, University of Pavia, Piazzale Golgi, 19 - 27100, Pavia, Italy

    Rachele Ciccocioppo

Authors
  1. Rachele Ciccocioppo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrizia Comoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandra Gallia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabrina Basso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fausto Baldanti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gino Roberto Corazza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rachele Ciccocioppo.

Additional information

Rachele Ciccocioppo and Patrizia Comoli equally contributed to the work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ciccocioppo, R., Comoli, P., Gallia, A. et al. Autologous Human Cytomegalovirus-Specific Cytotoxic T Cells as Rescue Therapy for Ulcerative Enteritis in Primary Immunodeficiency. J Clin Immunol 34, 681–685 (2014). https://doi.org/10.1007/s10875-014-0060-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-014-0060-1

Keywords

Search

Navigation