Hierarchic T‐Cell Help to Non‐Linked B‐Cell Epitopes

Abstract

The induction of antibodies against peptides requires the presence of a T helper cell epitope. In the absence of an added T-cell epitope only 10% of the mice, or less depending on the strain, gave an antibody response to a series of peptides of the measles virus (MV) fusion (F) protein. After coimmunization with a non-covalently coupled T-cell epitope more than 60% of the peptides became immunogenic. Considerable differences became apparent when BALB/c mice were immunized with peptides in the presence of different T-cell epitopes. An immunodominant T-cell epitope of the MV-F protein was more efficient than a subdominant or a cryptic T-cell epitope in providing help to a non-linked B-cell epitope. There is both a ranking order of the amount of help which B-cell epitopes require and a ranking order for the help T-cell epitopes are able to provide. The capability of a T-cell epitope to provide help to a B-cell epitope correlated with its own immunogenicity, i.e. the intensity of the antibody response to the peptide representing the T-cell epitope. The data suggest that for each MHC class II allele there is an optimal T-cell epitope which can provide help to a maximal number of B-cell epitopes and that such a peptide can be identified by its ability to induce antibodies against itself. By using this strategy, the authors were able to induce antibodies which cross-reacted with the MV.

Removal of B cell epitopes as a practical approach for reducing the immunogenicity of foreign protein-based therapeutics☆

“…4). Thus, the reduced immunogenicity we observed is due to alterations in B cell epitopes, as expected by the non-linkage between the locations of B cell epitopes and T cell epitopes [33, 34]. We suggest that removal of B cell epitopes reduces the immunogenicity likely independent of T cell epitopes and could be a robust deimmunization method that tolerates the high polymorphism of MHC.…”

“…In addition, the location of B cell epitopes is unconnected to that of the T cell epitopes [33, 34]. For effective deimmunization, B cell epitopes for high affinity antibodies should be given a high priority in the removal process.…”

Addressing the Immunogenicity of the Cargo and of the Targeting Antibodies with a Focus on Deimmunized Bacterial Toxins and on Antibody-Targeted Human Effector Proteins

“…T-cell epitopes are recognized by T-helper (Th) cells and are composed of peptide fragments derived from the antigen and of MHC (major histocompatibility complex) molecules [47]. Due to the variety of HLA (human leukocyte antigen) alleles in humans [48] and to the fact that T-cells stimulated by one epitope can initiate responses of numerous B-cell epitopes of the same antigen [49,50], it is a challenging task to eliminate all possible T-cell epitopes from an exogenous protein. Elimination of T-cell epitopes later became a well-accepted strategy for the deimmunization of therapeutic proteins [16,19,51,52,53,54,55].…”

Challenges for Therapeutic Application of Pseudomonas Exotoxin-Based Immunotoxins

“…This process is mediated by different intracellular signals and co-receptors, and occurs in secondary lymphoid organs, such as lymph nodes [78,79]. It should be stressed that the location of B cell epitopes does not fully overlap with the locations of the T cell epitopes on an immunogenic protein [80]. Ira Pastan's group at the NIH has been working for about a decade exploring the field of PE38 deimmunization while applying several approaches.…”