Kidney Allograft Tolerance in Primates Without Chronic Immunosuppression-the Role of Veto Cells

Thomas, Judith M.; Carver, F. Melinda; Cunningham, Paul; Olson, Les; Thomas, F

doi:10.1097/00007890-199101000-00032

Cited by 134 publications

(43 citation statements)

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“…The PCR-flow assay, combining the sensitivity of DNA amplification techniques with the detection of CD epitopes using monoclonal antibody flow cytometry analysis has now allowed for the detection of several specific cell lineages of donor origin in the recipient. It has the potential of eventually identifying the presence of such "facilitating cells" (35,36) and equating this with immunological unresponsiveness. The in vitro assays described in this report, however, have demonstrated nonspecific rather than donor specific immune inhibitory effects of the donor marrow, i.e., possibly because of nonspecific effects of "suppressor cell" subsets (33,37,38).…”

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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“…These subpopulations include "natural" suppressors 64 ; CD8 nonalloreactive T cells 65 ; CD8 ϩ , CD3 ϩ , CD45 R ϩ , Thy-1 ϩ , and TCR Ϫ "facilitator" cells 56 ; and CD2 ϩ , CD8 ϩ , CD16 ϩ , DR Ϫ , CD3 Ϫ , and CD38 Ϫ cells. 66 Thus, part of the effectiveness of our approach, using antigenspecific preexposure combined with anti-CD40 ligand blockade, high levels of marrow cells, and nonablative (100 cGy) host treatment, may be the infusion of appropriate numbers of tolerizing stem cells or tolerizing cells without stem cell potential. In addition, Ferrara 67 has described the phenomenon of "cytokine storm" occurring with cytoablative therapy and potentially inducing GVHD.…”

Section: Minimal Myeloablation and Murine Allochimerismmentioning

confidence: 99%

Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice

Quesenberry

Zhong

Wang

et al. 2001

Blood

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We have previously shown that the keys to high-level nontoxic chimerism in syngeneic models are stem cell toxic, nonmyelotoxic host treatment as provided by 100-cGy whole-body irradiation and relatively high levels of marrow stem cells. This approach was unsuccessful in H-2 mismatched B6.SJL to BALB/c marrow transplants, but with tolerization, stable multilineage chimerism was obtained. Ten million B6.SJL spleen cells were infused intravenously into BALB/c hosts on day ؊10 and (MR-1) anti-CD40 ligand monoclonal antibody (mAb) injected intraperitoneally at varying levels on days ؊10, ؊7, ؊3, 0, and ؉3 and the BALB/c mice irradiated (100 cGy) and infused with 40 million B6.SJL/H-2 mismatched marrow cells on day 0. Stable multilineage chimerism at levels between 30% to 40% was achieved in the great majority of mice at 1.6 mg anti-CD40 ligand mAb per injection out to 64 weeks after transplantation, without graft-versus-host disease. The transplanted mice were also tolerant of donor B6.SJL, but not third-party CBA/J skin grafts at 8 to 9 and 39 to 43 weeks after marrow transplantation. These data provide a unique model for obtaining stable partial chimerism in H-2 mismatched mice, which can be applied to various clinical diseases of man such as sickle cell anemia, thalassemia, and autoimmune disorders. (Blood. 2001;97:557-564)

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“…Veto cells suppress CTL precursor function against Ags present on the veto cell surface, but not against those on third-party allogeneic cells (28,29). Veto cells have been shown to prevent the rejection of allogeneic BM grafts in an Ag-specific manner (30).…”

mentioning

confidence: 99%

Veto-Like Activity of Mesenchymal Stem Cells: Functional Discrimination Between Cellular Responses to Alloantigens and Recall Antigens

Potian

Aviv

Ponzio³

et al. 2003

The Journal of Immunology

410

397

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Trans-differentiation of stem cells shows promise for use in tissue repair medicine. Although poorly defined, mesenchymal stem cells (MSC) appear useful for applications in repair medicine. Despite the low frequency of MSC, they are relatively easy to expand. The expression of MHC class II on MSC, however, could deter their use in repair medicine, since these molecules could stimulate an allogeneic host response. This study sought to compare the immune stimulatory and suppressive effects of MSC. Primary human MSC were cultured from bone marrow aspirates and then passaged at least three times before use in assays. Morphologically, MSC were symmetrical; were SH2+, MHC class II+, CD45−, CD44+, CD31−, CD14−, proly-4-hydroxylase−; and showed normal karyotype patterns and elevated telomerase activities. MSC elicited significant stimulatory responses when cocultured with allogeneic PBMC. Despite the production of different types of growth factors, allogeneic effects of MSC could not be explained by the production of these growth factors. One-way MLR reactions were significantly blunted by third-party MSC. Similar suppression was not observed for responses to three different recall Ags. Based on these functional differences by MSC in responses to allo- and recall Ags, we examined whether MSC could exert veto-like functions. We showed that MSC could blunt the cytotoxic effects of allogeneic-induced effectors to mitogen-activated targets. The results showed that although MSC elicited allogeneic responses in a model that mimics a graft-vs-host reaction, they also exerted veto-like activity, but caused no effect on responses to recall Ags.

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Kidney Allograft Tolerance in Primates Without Chronic Immunosuppression-the Role of Veto Cells

Cited by 134 publications

References 0 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.

Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice

Veto-Like Activity of Mesenchymal Stem Cells: Functional Discrimination Between Cellular Responses to Alloantigens and Recall Antigens

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