Treatment with low doses of polyclonal immunoglobulin improves B cell function during immune reconstitution in a murine model.
OBJECTIVE
[corrected] 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.
CEDOC, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Lisbon, Portugal.
Ana Barahona
AB
Afonso
Lígia Neves
LN
Justo
Ana Cristina
AC
Queirós
Constantin
C
Fesel
Maria Salomé
MS
Cabral
Maria Gomes
MG
da Silva
Luis
L
Porrata
Svetomir
S
Markovic
Ana Elisabete
AE
Pires
Cristina
C
João
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D018941:Antigens, CD19 / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D056724:Immunity, Humoral / Q000187:drug effects / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000008:administration & dosage / Q000276:immunology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007136:Immunoglobulins / Q000008:administration & dosage* / Q000276:immunology*; D016756:Immunoglobulins, Intravenous; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D013997:Time Factors; D014182:Transplantation, Autologous
D018941:Antigens, CD19; D053264:B-Cell Activating Factor; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007136:Immunoglobulins; D016756:Immunoglobulins, Intravenous; C505720:Tnfsf13b protein, mouse