Lotte Hougs

Human Memory B Cells Transferred by Allogenic Bone Marrow Transplantation Contribute Significantly to the Antibody Repertoire of the Recipient

The bone marrow is an important source of Abs involved in long-term protection from recurrence of infections. Allogenic bone marrow transplantation (BMT) fails to restore this working memory. Attempts to overcome this immunodeficiency by immunization of the donor have not been very successful. More needs to be known about transfer of B cell memory by BMT. We tracked memory B cells from the donor to the recipient during BMT of a girl with leukocyte adhesion deficiency. Vaccination of her HLA-identical sibling donor 7 days before harvest induced Haemophilus influenzae type b (Hib) capsular polysaccharide (HibCP)-specific B cells readily detectable in marrow and blood. BMT did not lead to spontaneous production of HibCP Abs, but the recipient responded well to booster immunizations 9 and 11 mo after BMT. HibCP-specific B cells were obtained 7 days after the vaccinations, and their VH genes were sequenced and analyzed for rearrangements and unique patterns of somatic hypermutations identifying clonally related cells. Ninety (74%) of 121 sequences were derived from only 16 precursors. Twelve clones were identified in the donor, and representatives from all of them were detected in the recipient where they constituted 61 and 68% of the responding B cells after the first and second vaccinations, respectively. No evidence for re-entry of memory clones into the process of somatic hypermutation was seen in the recipient. Thus, memory B cells were transferred from the donor, persisted for at least 9 mo in the recipient, and constituted the major part of the HibCP-specific repertoire.

Knocking out IL-6 by vaccination.

Inappropriate expression of IL‐6 plays a role in various inflammatory conditions, degenerative diseases, and cancers. Several model systems have been developed that can specifically block IL‐6‐receptor interactions. Here we present a simple and highly effective approach based on vaccination with a pool of specifically mutated IL‐6 analogues to induce a neutralizing IL‐6 antibody responsein mice. Judged by the ability of the analogues to bind to heterologous anti‐IL‐6 antibodies and cellular IL‐6 receptors the IL‐6 analogues seemed to have a three‐dimensional structure comparable to that of wild‐type IL‐6. Injection of them broke self‐tolerance and induced an immune response to IL‐6, presumably because of the amino acid differences between the analogues and wild‐type IL‐6. This resulted in a long‐lasting anti‐IL‐6 antibody‐mediated IL‐6 deficiency that blocked experimentally induced IL‐6‐mediated pathology.

A NEW APPARENTLY FUNCTIONAL IGVK GENE (VKLA) PRESENT IN SOME INDIVIDUALS ONLY

Abstract We describe a hitherto unknown functional IGKV gene, VkLa, belonging to the IGKV1 subgroup with exon 2 having only 94% similarity to the closest known IGKV gene, 1–13/1D-13 (L4/L18a). Genomic DNA sequences spanning from 5’ of the decanucleotide box to 3’ of the heptamer (649 bp) were cloned and sequenced from four individuals. The new gene encodes the conserved amino acids in the exons and contains no apparent defects in known regulatory intron sequences such as pd-box, dc-box, TATA-box, CCCT-elements, splice-sequences, initiation codon, and heptamer sequence. VkLa is therefore potentially functional and, correspondingly, we found transcripts of properly rearranged VkLa with somatical hypermutations. VkLa was found in 12 of 57 (21%) healthy Caucasians by a nested polymerase chain reaction and subsequent sequencing of exon 2. This finding shows that there is more inter-individual variation in the available IGKV gene repertoire than was hitherto assumed. Finally, we describe a minor correction in the IGKV1D-43 (L23) gene sequence.