Somatically mutated regions of immunoglobulin on human B-cell lymphomas code for peptides that bind to autologous major histocompatibility complex class I, providing a potential target for cytotoxic T cells.

Lymphoma-derived immunoglobulin idiotype (Id) is a well-characterized, tumor-specific antigen on B-cell malignancies. Immunotherapy using lymphoma immunoglobulin can lead to clinical responses mostly associated with anti-Id antibody. We cloned the Id from B-cell lymphomas, sequenced them, and used bioinformatics to select autologous MHC class I binding peptides from somatically mutated regions of the lymphoma Id. Peptides from patients who were HLA-A1, HLA-A2, HLA-A3, or HLA-A11 positive were analyzed in the T2 stabilization assay and a competitive peptide-binding assay. By both methods, approximately half of the peptides analyzed, regardless of HLA type, bound with intermediate or high affinity. Peptide binding affinity was similar to viral peptide sequences known to provide targets for cytotoxic T cells. Further investigation of lymphocyte responses to stimulation by autologous Id peptides versus Id peptides from other patients revealed that three of five patients in complete remission or with low volume, stable disease responded to self-peptides by IFN-gamma secretion greater than that seen with non-self peptides, whereas none of five patients with progressive disease responded to their own lymphoma Id. We have shown that mutated regions of lymphoma Id contain MHC class I binding peptides that are potential targets for cytotoxic T cells. Immunotherapy using the tumor-specific mutated regions from lymphoma Id avoids the need to break innate tolerance toward the germ-line protein sequences present on normal and malignant B cells.

Immunoglobulin heavy-chain gene rearrangement in adult acute lymphoblastic leukemia reveals preferential usage of J(H)-proximal variable gene segments.

The aim of this study was to characterize individual-segment and overall patterns of V(H) gene usage in adult B-lineage acute lymphoblastic leukemia (ALL). Theoretical values of V(H) segment usage were calculated with the assumption that all V(H) segments capable of undergoing rearrangement have an equal probability of selection for recombination. Leukemic clones from 127 patients with adult B-lineage acute leukemias were studied by fingerprinting by means of primers for the framework 1 and joining segments. Clones from early preimmune B cells (245 alleles identified) show a predominance of V(H)6 family rearrangements and, consequently, do not conform to this hypothesis. However, profiles of V(H) gene family usage in mature B cells, as investigated in peripheral blood (6 samples), B-cell lymphomas (36 clones) and chronic lymphocytic leukemia (56 clones), are in agreement with this theoretical profile. Sequence analyses of 64 V(H) clones in adult ALL revealed that the rate of V(H) usage is proportional to the proximity of the V(H) gene to the J(H) locus and that the relationship can be mathematically defined. Except for V(H)6, no other V(H) gene is excessively used in adult ALL. V(H) pseudogenes are rarely used (n = 2), which implies the existence of early mechanisms in the pathway to B-cell maturation to reduce wasteful V(H)-(D(H))-J(H) recombination. Finally, similar to early immunoglobulin-H rearrangement patterns in the mouse, B cells of ALL derive from a pool of cells more immature than the cells in chronic lymphoid B-cell malignancies.