GENETICALLY TRANSFERRED CENTRAL AND PERIPHERAL IMMUNE TOLERANCE VIA RETROVIRAL-MEDIATED EXPRESSION OF IMMUNOGENIC EPITOPES IN HEMATOPOIETICPROGENITORS OR PERIPHERAL B-LYMPHOCYTES
Et. Zambidis et al., GENETICALLY TRANSFERRED CENTRAL AND PERIPHERAL IMMUNE TOLERANCE VIA RETROVIRAL-MEDIATED EXPRESSION OF IMMUNOGENIC EPITOPES IN HEMATOPOIETICPROGENITORS OR PERIPHERAL B-LYMPHOCYTES, Molecular medicine, 3(3), 1997, pp. 212-224
Citations number
46
Categorie Soggetti
Biology,"Medicine, Research & Experimental","Cell Biology
Background: Based on the hypothesis that IgGs are potent tolerogens an
d that immature lymphohematopoietic antigen-presenting cells (APC), an
d even mature peripheral B cells, may be effective APC for tolerance i
nduction, we designed an immunoglobulin fusion protein retroviral expr
ession vector to test the role of B cells in a novel gene therapy stra
tegy for the transfer of immune tolerance. Methods: An immunodominant
epitope (residues 12-26 of the lambda repressor cI protein) was fused
in Game to an IgG heavy chain in a retroviral vector, which was used t
o infect either bone marrow cells or activated peripheral B lymphocyte
s. These cells were transferred into syngeneic recipients, who were su
bsequently challenged with the 12-26 peptide in adjuvant. Results: Bon
e marrow (BM) chimeras generated with retrovirally transduced bone mar
row were shown to be profoundly unresponsive to the 12-26 peptide at b
oth the humoral and cellular levels, but were competent to respond to
an unrelated protein (lysozyme or PPD). Importantly, we also show that
immunocompetent adult recipients infused with transduced mature, acti
vated B lymphocytes, are rendered unresponsive by this treatment. Surp
risingly, lymphoid-deficient BM progenitors from syngeneic SCID donors
could also be transduced to produce tolerogenic APC. Conclusions: Our
data suggest that activated B cells are sufficient to be effective to
lerogenic APC in immunocompetent adult mice, but that nonlymphoid cell
s may also induce tolerance in reconstituted hosts. This approach for
gene-transferred tolerogenesis has the potential to be maintained inde
finitely, and it requires only knowledge of cDNA sequences of target a
ntigens.