Fulminant experimental autoimmune encephalo-myelitis induced by retrovirally mediated TCR gene transfer

Stolzer, Amy; Sadelain, Michel; Sant’Angelo, Derek B.

doi:10.1002/eji.200526123

Cited by 3 publications

(4 citation statements)

References 41 publications

(54 reference statements)

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“…Several envisioned gene therapy applications require expression of multiple proteins in T cells. The most obvious of these would be the introduction of pre-rearranged TCRα and TCRβ chains that, together, would encode a receptor targeting diseased cells [32]–[34].…”

Section: Discussionmentioning

confidence: 99%

Ectopic T Cell Receptor-α Locus Control Region Activity in B Cells Is Suppressed by Direct Linkage to Two Flanking Genes at Once

et al. 2010

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The molecular mechanisms regulating the activity of the TCRα gene are required for the production of the circulating T cell repertoire. Elements of the mouse TCRα locus control region (LCR) play a role in these processes. We previously reported that TCRα LCR DNA supports a gene expression pattern that mimics proper thymus-stage, TCRα gene-like developmental regulation. It also produces transcription of linked reporter genes in peripheral T cells. However, TCRα LCR-driven transgenes display ectopic transcription in B cells in multiple reporter gene systems. The reasons for this important deviation from the normal TCRα gene regulation pattern are unclear. In its natural locus, two genes flank the TCRα LCR, TCRα (upstream) and Dad1 (downstream). We investigated the significance of this gene arrangement to TCRα LCR activity by examining transgenic mice bearing a construct where the LCR was flanked by two separate reporter genes. Surprisingly, the presence of a second, distinct, reporter gene downstream of the LCR virtually eliminated the ectopic B cell expression of the upstream reporter observed in earlier studies. Downstream reporter gene activity was unaffected by the presence of a second gene upstream of the LCR. Our findings indicate that a gene arrangement in which the TCRα LCR is flanked by two distinct transcription units helps to restrict its activity, selectively, on its 5′-flanking gene, the natural TCRα gene position with respect to the LCR. Consistent with these findings, a TCRα/Dad1 locus bacterial artificial chromosome dual-reporter construct did not display the ectopic upstream (TCRα) reporter expression in B cells previously reported for single TCRα transgenes.

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Section: Discussionmentioning

confidence: 99%

Ectopic T Cell Receptor-α Locus Control Region Activity in B Cells Is Suppressed by Direct Linkage to Two Flanking Genes at Once

et al. 2010

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“…Delivery of tumor-specific TCR genes into hematopoietic stem cells constitutes a recent promising strategy in this direction (7,8). Antigen-specific T cells may also be provided by infusion of lymphoid progenitors that are educated and tolerized according to the recipient's genetic background (45).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, a major limitation of T cell transgenesis is the difficulty in teasing apart the postdevelopmental functions of genes from effects on T cell development, when transgenes are placed under the control of T lineage enhancer/promoters, such as those derived from the Lck, Cd4, or CD2 genes (4)(5)(6). Segregating thymic versus post-thymic effects of transgene expression would also be useful to target gene products such as tumor antigen-specific TCRs to post-thymic T cells without perturbing thymocyte development and selection, which could result from the expression of autoreactive, high-affinity TCRs (7,8).…”

Section: Introductionmentioning

confidence: 99%

Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras

et al. 2008

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MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression by targeting complementary sequences, referred to as miRNA recognition elements (MREs), typically located in the 3′ untranslated region of mRNAs. miR-181a is highly expressed in developing thymocytes and markedly downregulated in post-thymic T cells. We investigated whether endogenous miR-181a can be harnessed to segregate expression of chimeric antigen receptors (CARs) and TCRs between developing and mature T cells. Lentiviral-encoded antigen receptors were tagged with a miR-181a-specific MRE and transduced into mouse BM cells that were used to generate hematopoietic chimeras. Expression of a CAR specific for human CD19 (hCD19) was selectively suppressed in late double-negative and double-positive thymocytes, coinciding with the peak in endogenous miR-181a expression. Receptor expression was fully restored in post-thymic resting and activated T cells, affording protection against a subsequent challenge with hCD19 + tumors. Hematopoietic mouse chimeras engrafted with a conalbumin-specific TCR prone to thymic clonal deletion acquired peptide-specific T cell responsiveness only when the vector-encoded TCR transcript was similarly engineered to be subject to regulation by miR-181a. These results demonstrate the potential of miRNA-regulated transgene expression in stem cell-based therapies, including cancer immunotherapy.

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“…137,138 T cells expressing ␥␦TCR are another lymphocyte population with endogenous killing ability that has been modified to express CAR, and these cells can be selectively proliferated using an aminobiphosphonate (Zoledronate), 139 raising the possibility that a Food and Drug Administration (FDA)-approved pharmacologic agent can be used to selectively propagate these infused CAR ϩ T cells in vivo. Instead of genetically modifying mature lymphocytes to express CAR, investigators have introduced CAR into developing thymocytes 140 and immunoreceptors into hematopoietic stem cells (HSC) [141][142][143] to avoid negative selection and improve immune-mediated surveillance. The approach of genetically modifying lymphoid precursors has also been adapted by Zakrzewski et al to make "universal T cells" in which CAR ϩ HSC can be adoptively transferred across MHC barriers.…”

Section: Expressing Cars In Cells Other Than ␣␤ Tcr ؉ T Cellsmentioning

confidence: 99%

Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor

Jena

Dotti

Cooper

2010

Blood

260

210

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Fulminant experimental autoimmune encephalo-myelitis induced by retrovirally mediated TCR gene transfer

Cited by 3 publications

References 41 publications

Ectopic T Cell Receptor-α Locus Control Region Activity in B Cells Is Suppressed by Direct Linkage to Two Flanking Genes at Once

Ectopic T Cell Receptor-α Locus Control Region Activity in B Cells Is Suppressed by Direct Linkage to Two Flanking Genes at Once

Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras

Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor

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