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Treatment with Low Doses of Polyclonal Immunoglobulin Improves B Cell Function During Immune Reconstitution in a Murine Model

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Abstract

Propose

After autologous stem cell transplantation (ASCT) the immunological B cell compartment recovers slowly. Delays on the recovery of B cell function after autologous stem cell transplantation are due to the low lymphocytes count and to their intrinsic dysfunction.

Methods

We studied the in vivo B cell reconstitution after ASCT examining the independent effect of polyclonal IgG (PolyIg), Fab or Fc fragments infusions in a murine animal model during a period of 12 weeks. These molecules were used in low doses, mimicking the recommended use of IVIg in the case of hypogammaglobulinemia in humans. Flow cytometry analysis and ELISA tests were conducted to monitor the reconstitution of B cells and serum immunoglobulin production. Panama blot and PCA factor 1 analysis were used to study the kinetics of immunoglobulin repertoires reconstitution. Mechanistic studies were also performed using in vitro cell culture.

Results

During follow-up after ASCT, peripheral B cells expand independently of treatment, correcting the immediate increase in sBAFF (soluble B cell activating factor) induced by previous intense myeloablation. Treatments with Fab and Fc fragments infusions promote significant IgM and IgG production comparing to control. Although the complete recovery of antibody repertoire is only achieved at the end of follow-up after ASCT, there is an earlier and significantly stronger recovery in the treated mice, which is evident at 9 weeks after ASCT. At 30 weeks after ASCT, normal values of antibody repertoire were detected in all individuals. Mechanistic studies show that Fab and Fc fragments promote IgG1 production by indirect pathways.

Conclusions

The results presented here demonstrate that polyclonal immunoglobulin indirectly improves the function of the reconstituted B cells and their IgG production by means of Fc-mediated effects on bystander cells. These results further stimulate the discussion about the advantages of IVIg therapy during immune reconstitution after human ASCT.

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Acknowledgments

The authors would like to thank Isabel Gordo, Nuno Costa and Vasco Barreto, from Instituto Gulbenkian de Ciência, for providing E. coli bacteria and detailed protocols for its growth; for helping with flow cytometry analyses and animal handling; and for providing advice to perform B cell cultures.

We would like also to thank Teresa Faria, from Instituto Português de Oncologia, for helping with flow cytometry analyses and to Diane Jelinek and Xiaosheng Wu, from Mayo Clinic, for valuable discussions regarding the importance of the JHT experiments.

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Authors and Affiliations

  1. CEDOC, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Lisbon, Portugal

    Ana Barahona Afonso, Lígia Neves Justo, Ana Cristina Queirós, Maria Gomes da Silva, Ana Elisabete Pires & Cristina João

  2. Instituto Gulbenkian Ciência, Oeiras, Portugal

    Constantin Fesel

  3. Centro de Estatística e Aplicações, Faculdade de Ciências, Departamento de Estatística e Investigação Operacional, Universidade de Lisboa, Lisbon, Portugal

    Maria Salomé Cabral

  4. Departamento de Hematologia, Instituto Português de Oncologia Francisco Gentil de Lisboa, Prof. Lima Basto, 1099-023, Lisbon, Portugal

    Maria Gomes da Silva & Cristina João

  5. Internal Medicine Department, Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Luis Porrata & Svetomir Markovic

  6. Grupo de Biologia Molecular, Instituto Nacional de Investigação Agrária e Veterinária, I.P. & Centro de Biologia Ambiental, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal

    Ana Elisabete Pires

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  1. Ana Barahona Afonso
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  2. Lígia Neves Justo
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  3. Ana Cristina Queirós
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  4. Constantin Fesel
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  7. Luis Porrata
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  9. Ana Elisabete Pires
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  10. Cristina João
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Correspondence to Cristina João.

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Afonso, A.B., Justo, L.N., Queirós, A.C. et al. Treatment with Low Doses of Polyclonal Immunoglobulin Improves B Cell Function During Immune Reconstitution in a Murine Model. J Clin Immunol 33, 407–419 (2013). https://doi.org/10.1007/s10875-012-9802-0

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  • DOI: https://doi.org/10.1007/s10875-012-9802-0

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