Disease relevance of Clonal Deletion

• However, the significance of B7-mediated clonal deletion in preventing autoimmune diseases has not been studied systematically [1].
• This Mls-1a-like clonal deletion is associated neither with the expression of an Mls-1a-like antigen that could be identified in mixed lymphocyte reaction in vitro, nor with the presence of Mtv-7, the endogenous mouse mammary tumor virus (MMTV) proviral loci [2].
• The escape from clonal deletion and subsequent reactivation of autoimmune T cells which we observed in V beta 8.1 TCR-transgenic mice can be a model for human autoimmune diseases such as multiple sclerosis and type I diabetes, in which T cells are directed against a specific autoantigen [3].
• Identification of an endogenous mammary tumor virus involved in the clonal deletion of V beta 2 T cells [4].
• Female C3H/HeJ mice maternally transmit through their milk an infectious mouse mammary tumor retrovirus (MMTV) which causes clonal deletion of T cell receptor (TcR)V beta 14+ T cells reactive to the retroviral superantigen (SAG) [5].

High impact information on Clonal Deletion

• If allogeneic marrow is given at high cell doses under the umbrella of CD4 and CD8 antibodies, then tolerance can be achieved through clonal deletion [6].
• We show here that transmission of an infectious MMTV is prevented when superantigen-reactive cells are absent through either clonal deletion due to the expression of an endogenous MTV with identical superantigen specificity or exclusion due to expression of a transgenic TCR beta chain that does not interact with the viral superantigen [7].
• CD4+ cells are positively selected in K14 mice, but clonal deletion does not ocur in K14 mice or in relB-negative mice, which lack a thymic medulla [8].
• The effects of two PTK-specific inhibitors, herbimycin A and genistein, on the clonal deletion of immature thymocytes and the activation of mature thymocytes were examined [9].
• Gene dosage--limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity [10].

Biological context of Clonal Deletion

• Distinct recognition phenotypes exist for T cell clones specific for small peptide regions of proteins. Implications for the mechanisms underlying major histocompatibility complex-restricted antigen recognition and clonal deletion models of immune response gene defects [11].
• Functional clonal deletion in immunological tolerance to major histocompatibility complex antigens [12].
• Extrathymic T cell tolerance to Ags can be achieved through clonal deletion by activation-induced programmed cell death as well as by functional unresponsiveness (anergy) of Ag reactive-T cells [13].
• Thymocyte chimerism and extensive clonal deletion of mature V beta 11+ B10 thymocytes were observed as early as 10 days post-BMT and at all subsequent time points in thymi of mixed chimeras [14].
• As in clonal deletion models, and as predicted by the down-regulation of NF-kappa B, PAH-induced death of pro/pre-B cells was at least partially dependent on c-Myc down-regulation [15].

Anatomical context of Clonal Deletion

• Pharmacological doses of the GC agonist dexamethasone (DEX) alter the in vivo response of splenic V beta 8+ T cells to SEB, thus impeding the expansion of such cells and causing their rapid (3 d) clonal deletion [16].
• These results indicate that lpr-derived T cells escape not only tolerance-related clonal deletion but also some induction of unresponsiveness in the non-lpr thymus [17].
• The critical role of B7-1 and B7-2 in T cell clonal deletion may explain, at least in part, the paradoxical increase of autoimmune disease in mice deficient for this family of costimulatory molecules, such as cytotoxic T lymphocyte associated molecule 4, CD28, and B7-2 [1].
• In contrast, self-antigen-induced clonal deletion of mature self-reactive Ly-1 B (B1) cells in the peritoneal cavity was inhibited in the transgenic mice [18].
• Here, the author reviews recent evidence demonstrating that inhibition of c-myc expression activates apoptosis of B cell models of clonal deletion and that rescue from apoptosis by CD40 ligand leads to maintenance of c-Myc levels [19].

Associations of Clonal Deletion with chemical compounds

• In conclusion, these results show that (a) natural tolerance to C5 is an active process that is T cell dependent and requires the presence of antigen; (b) in this natural model, clonal abortion does not seem to occur; and (c) both tolerant and nontolerant B cells retain the capacity to produce autoantibody [20].
• Sequential mechanisms of cyclophosphamide-induced skin allograft tolerance including the intrathymic clonal deletion followed by late breakdown of the clonal deletion [21].
• Relationship of cyclosporine A-mediated inhibition of clonal deletion and development of syngeneic graft-versus-host disease [22].
• Our results also confirm the previous findings that accessory molecules on thymocytes such as CD4 may be involved in thymic selection, and further suggest that an interaction of mousE CD4 and mouse A alpha chain is required for the clonal deletion [23].
• Unlike control animals, RV-gp chimeric animals did not possess T cells specific for the gp Ag as measured by proliferation and cytotoxic function, and further analysis suggested that tolerance of the gp-specific self-reactive T cells occurred by clonal deletion [24].

Gene context of Clonal Deletion

• Nonresponsiveness could be reversed by culture in IL-2, indicating that anergy, and not clonal deletion, is responsible for this phenomenon [25].
• Here we report that the perinatal blockade of B7-1 and B7-2 substantially inhibits the clonal deletion of T cells in the thymus and leads to an accumulation of T cells capable of inducing fatal multiorgan inflammation [1].
• A number of in vitro studies have suggested that costimulatory molecules B7-1 and B7-2 and their receptor CD28 can promote clonal deletion, and limited in vivo studies have indicated that CD28 is involved in the clonal deletion of some T cells [1].
• Together, these results show that in addition to clonal deletion, self-recognition by immature thymocytes leads to phenotypic maturation of a small subset of thymocytes expressing IL-2R beta [26].
• Interaction of Fas with Fas ligand (FasL) is known to play a role in peripheral tolerance mediated by clonal deletion of Ag-specific T cells [27].

Analytical, diagnostic and therapeutic context of Clonal Deletion

• Regulation of thymocyte development through CD3. I. Timepoint of ligation of CD3 epsilon determines clonal deletion or induction of developmental program [28].
• Spleen cells from recipients bearing intact grafts led to rejection of rat islet xenografts in scid mice, suggesting that graft acceptance was not due to complete clonal deletion of xenoreactive cells [29].
• Recipients were assayed for suppressor cell activity (mixed lymphocyte coculture assays), clonal deletion (T-cell receptor Vbeta11 assay), peripheral and thymic chimerism (flow cytometry and reverse transcriptase polymerase chain reaction), and anergy (response to exogenous interleukin 2) [30].
• It should be possible to utilize this enhanced activity for increased clonal deletion if pulse cyclophosphamide is applied shortly after plasmapheresis [31].
• Therefore, we have proposed a new concept of 'clonal deletion' therapy with acyclic retinoid for the cancer chemoprevention against HCC [32].

References