| Project/Area Number |
05807051
|
|---|
| Research Category |
Grant-in-Aid for General Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
Gastroenterology
|
|---|
| Research Institution | KEIO UNIVERSITY |
|---|
Principal Investigator |
WATANABE Mamoru KEIO UNIVERSITY,SCHOOL OF MEDICINE,INSTRUCTOR, 医学部, 助手 (10175127)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
HIBI Toshifumi KEIO CANCER CENTER,ASSOCIATE PROFESSOR, 助教授 (50129623)
AISO Sadakazu KEIO UNIVERSITY,SCHOOL OF MEDICINE,PROFESSOR, 医学部, 教授 (60138013)
|
|---|
| Project Period (FY) |
1993 – 1994
|
| Project Status |
Completed (Fiscal Year 1994)
|
| Budget Amount *help |
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1994: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1993: ¥1,000,000 (Direct Cost: ¥1,000,000)
|
|---|
| Keywords | AIDS / HIV / INTESTINAL MUCOSAL LYMPHOCYTE / CYTOTOXIC T LYMPHOCYTE / CD4 / MONOCLONAL ANTIBODY / SOLUBLE CD4 / 腸管上皮間リンパ球 |
|---|
| Research Abstract |
Two distinct approaches to active, specific immune therapy for AIDS were explored in nonhuman primates. Studies were done to assess the feasibility of targeting the T-cell receptor (TCR) of AIDS virus-specific cytotoxic T lymphocytes (CTL) to facilitate expansion of that cell population in vivo. Experiments were also performed to determine the possibility of inducing an anti-self CD4 antibody response through immunization as a means of inhibiting HIV replication in infected individual.
It recently has been shown that TCR-targeted interventions can alter disease pathogenesis in model systems in which restricted T lymphocyte populations play an important part in disease induction. To explore the feasibility of such an intervention a therapeutic strategy in AIDS.We sought to determine whether there is a diverse or restricted usage of T-cell receptors by SIVmac-specific CTL established from intestinal mucosal lymphocytes. Six gag-specific cytotoxic T lymphocytes (CTL) clones from intestinal
… More
mucosal lymphocytes were independently generated from a simian immunodeficiency virus of macaques (SIVmac) -infected rhesus monkey. All 6 CTL clones recognized a single SIV gag peptide in association with a single major histocompatibility complex (MHC) class I gene product, Mamu-A 0.1. TCR-alpha chain sequences from theses 6 CTL clones employed four different Valpha and five different Jalpha gene families. In contrast, 5 of the 6 C T L clones expressed Vbeta genes that were members of the same family, a human Vbeta23 homologue. Furthermore, a single Jbeta gene was expressed by 4 of the 6 CTL clones. These results indicate that TCRs of SIVmac gag-specific CTL exhibited a restricted usage of Vbeta and Jbeta families. This observations raises the possibility that a restricted population of mucosal lymphocytes employing a single TCR response to the AIDS virus.
We have also recently begun exploring the use of rsCD4 as an immunogen in AIDS therapy. We previously reported that SIVmac-infected monkeys immunized with human recombinant soluble CD4 (rsCD4) developed an anti-rhesus monkey CD4 antibody response. Coincident with the development of this anti-self CD4 antibody response, SIVmac could not be isolated from peripheral blood lymphocytes (PBLs) and bone marrow macrophages of these animals. We wanted to translate theses findings in the rhesus to an animal madel which more closely approximates humans. We therefore, chose to study the chimpanzee, since its lymphocytes are readily infected by HIV-1 and its CD4 molecule differs from man's at only 4 amino acid residues. We demonstrated that immunization of chimpanzees with rsCD4 elicits an anti-self CD4 antibody response. This antibody blocks HIV replication in chimpanzee and human lymphocytes without inducing immune dysfunction in the chimpanzees. These observations suggest that rsCD4immunization of HIV-infected individuals may be feasible and therapeutically beneficial. Less
|
