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which are subsequently transported to the surface, where they engage T cells. T cells
require the presentation of the MHC:peptide complex and engagement of
CD28:CD80/CD86 (Signal 1 and 2) to become activated.
Returning to the case of the B cell, following ingestion of a protein therapeutic by
a B cell, the protein is also processed as described above. HLA Class II-peptide
complexes are then transported to the surface of the B cell, where they are exposed
to interrogation by passing CD4
+
T cells (Signal 1), causing the epitope-specific
CD4
+
to secrete selected cytokines such as gamma-interferon, IL-2, IL-4, and IL-10.
Signal 2 is provided by the engagement of the CD40:CD154 proteins on the B cell
and T-cell, respectively. These two signals are followed by Signal 3, the release of
cytokines from the T cells, initiating a cascade of further immunostimulatory events.
The cytokines cause B cells to expand and undergo phenotypic changes resulting in
the establishment of memory B cells.
6.2.3.3 Absence of T Help Abrogates Ab Formation
The binding of peptide epitopes (derived from internal processing of proteins by B
cells) to HLA Class II molecules and the recognition of the epitope-HLA complex by
activated helper T cells are necessary components of any T-cell-dependent antibody
response. Without Signal 2 provided by the cytokines released as a result of T-cell
interaction, the naïve B-cell response does not mature. Without T-cell help, activa-
tion of B cells to antibody-secreting plasma cells can only occur in the presence of
aggregates or polymeric proteins (T-cell-independent activation). Attenuation of the
helper T-cell response to immunogenic peptides derived from therapeutic proteins
has therefore become the focus of considerable research effort.
Since the T-cell epitope plays a critical role in the development of T-cell-
dependent antibody responses, it stands to reason that protein sequence modifications
that result in the removal of potential T-cell epitopes from autologous (recombinant
therapeutic) proteins could indeed reduce the potential for induction of an immune
response against the protein. Loss of T-cell help removes Signal 2 for B cells ex-
pressing receptor specificity for a therapeutic protein. In theory, loss of Signal 2 due
to epitope modification could actually induce B-cell apoptosis and/or tolerance
(Kappler, Roehm, and Marrack 1987).
6.2.3.4 Effect of Pegylation and Glycosylation
Pegylation and glycosylation are two commonly used approaches to solving the
immunogenicity problem. Polyethylene glycol (PEG) conjugates of protein antigens
appear to induce antigen-specific immune tolerance either by masking B-cell epi-
topes (B-cell Signal 1, structural interference), by stabilizing the protein antigen and
increasing the duration of exposure to the antigen (thereby inducing tolerance), or by
directly interfering with the processing and presentation of T-cell epitopes to T
H
cells
(B-cell Signal 1) (So, Ito, Koga, Watanabe, Ueda, and Imoto 1997).
Like pegylation, glycoslyation decreases plasma clearance of therapeutic and
increases the half-life of the protein molecules. The primary impact of glycosylation
is to interfere with antibody affinity (B-cell Signal 1). No information is available on
