Idiotypic Manipulation of the Immune Response to Transplantation Antigens

Bluestone, Jeffrey A.; Léo, Oberdan; Epstein, Suzanne L.; Sachs, David H.

doi:10.1111/j.1600-065x.1986.tb01475.x

Cited by 20 publications

(2 citation statements)

References 34 publications

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“…In the setting of tolerance induced in the fetal (or newborn) mouse (21), chimerism has always been synonymous with a state of permanent and lifelong specific unresponsiveness to donor tissue alloantigens, i.e., chimerism equaled tolerance, with the caveat of the intrusive presence of graft versus host disease (25). However, with the development of other experimental transplant models predominantly in rodents (26)(27)(28), it became evident that several mechanisms of inducing unresponsiveness to alloantigens could be used without the necessity for extensive and dominant donor bone marrow lineage chimerism (although "microchimerism" may have been present as a result of such cells migrating out of the graft) (29). This has given rise to vigorous controversy as to whether the presence of microchimerism is a cause or an effect of donor alloantigen specific unresponsive states (30, 31).…”

Section: Discussionmentioning

confidence: 99%

The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients.

et al. 1997

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Abstract40 recipients of first cadaver kidney transplants were given perioperative donor vertebral bone marrow infusions (DBMC), compared with 100 controls who did not receive donor bone marrow. The immunosuppressive regimen included OKT3, Tacrolimus, and steroid maintenance therapy, and, in some patients, newly introduced mycophenolate mofetil. This report describes the 24-mo actuarial follow-up and several immunological monitoring studies including sequential measurements of donor bone marrow lineage subset chimerism by the recently reported PCR-flow assay. This is a sensitive in situ PCR detection system for donor versus recipient histocompatibility genes as well as cell surface CD epitope markers using flow cytometry. The results indicate ( a ) the stabilization of the donor CD3 ϩ and CD34 ϩ cells in recipient peripheral blood at levels below 1% between 6 mo and 1 yr postoperatively, with a 10-fold higher level of donor cell chimerism of these lineages in recipient iliac crest marrow; ( b ) significantly lower levels of chimerism in peripheral blood up to 6 mo postoperatively in patients who had early acute (reversible) rejection episodes compared with those who did not; ( c ) a higher degree of chimerism seen in patients who were class II MHC HLA DR identical with their donors; ( d ) the identification of a high proportion of the donor bone marrow derived CD3 dimly staining subset of T cells (to which regulatory functions have been ascribed) in recipient peripheral blood and especially in recipient bone marrow; and ( e ) an unexpectedly increased susceptibility to clinically significant infections (primarily viral), and even death in the DBMC-infused group, compared with controls, but no graft losses because of rejection in the DBMC-infused group. Mixed lymphocyte culture assays showed a trend toward a greater number of nonspecifically low reactors in the DBMC group, as well as a greater number of nonspecifically high reactors in the controls ( P ϭ 0.058). The autologous mixed lymphocyte reaction also indicated a trend towards nonspecific immune activation in the DBMC group. Finally, anti-cytomegaloviral IgG antibody reactivity was significantly inhibited in the DBMC group 4-6 mo postoperatively ( P ϭ Ͻ 0.05). In the controls, there were no donor cell lineages detected by PCR-flow in the peripheral blood. These rather unexpected findings, indicating a more depressed cellular and humoral immune capacity in the DBMC cadaver kidney transplant recipients in this relatively early follow-up period, are discussed relevant to chimerism, MHC restriction, and suppressor activity brought about by specialized DBMC subsets, which still need to be defined. ( J. Clin. Invest. 1997. 99:1118-1129.)

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Section: Discussionmentioning

confidence: 99%

The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients.

et al. 1997

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“…Thus, the difference in the development of graft tolerance with PBL or BM might be the consequence of an intrinsic difference in their ability to engraft the recipient's tissues. Controversy exists, however, about whether microchimerism is a cause or a consequence of the donor alloantigen-specific unresponsive state (13,23,42).…”

Section: Discussionmentioning

confidence: 99%

Thymic Microchimerism Correlates with the Outcome of Tolerance-Inducing Protocols for Solid Organ Transplantation

Noris

Cugini

Casiraghi

et al. 2001

Journal of the American Society of Nephrology

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ABSTRACT. This study found that pretransplant infusion of donor peripheral blood leukocytes, either total leukocytes (peripheral blood leukocytes) or peripheral blood mononuclear cells (PBMC), under appropriate immunomodulating conditions was more effective than donor bone marrow (BM) in prolonging the survival of rats that received kidney grafts. A higher percentage of MHCII+ cells was found in donor PBMC than in BM cells, and depletion of MHCII+ cells from donor PBMC abolished their tolerogenic potential. By the analysis of microchimerism in rats infused with donor cells and killed at different time points thereafter, the better tolerogenic potential of leukocyte infusion related to a higher capability of these cells to engraft the recipient thymus. PCR analysis on OX6-immunopurified cells revealed the presence of donor MHCII+ cells in the thymus of these animals. The role of intrathymic microchimerism was reinforced by findings that thymectomy at the time of transplant prevented tolerance induction by donor leukocytes. Donor DNA was found in the thymus of most long-term graft animals that survived, but in none of those that rejected their grafts. The presence of intrathymic microchimerism correlated with graft survival, and microchimerism in other tissues was irrelevant. PCR analysis of DNA from thymic cell subpopulations revealed the presence of donor MHCII+ cells in the thymus of long-term surviving animals. Thus, in rats, donor leukocyte infusion is better than donor BM for inducing graft tolerance, defined by long-term graft survival, donor-specific T cell hyporesponsiveness, and reduced interferon gamma production. This effect appears to occur through migration of donor MHCII+ cells in the host thymus.

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DNA Antibodies and Idiotypes

Isenberg

1989

Current Therapy in Nephrology

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Idiotypic Manipulation of the Immune Response to Transplantation Antigens

Cited by 20 publications

References 34 publications

The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients.

The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients.

Thymic Microchimerism Correlates with the Outcome of Tolerance-Inducing Protocols for Solid Organ Transplantation

DNA Antibodies and Idiotypes

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