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Transgene-specific host responses in cutaneous gene therapy: the role of cells expressing the transgene.

ABSTRACT: A major issue in long-term gene therapy is host immune responses to therapeutic cells when transgene encodes a potential antigen. The nature of these responses depends on several factors including the type of cell and tissue expressing the transgene. Keratinocytes and fibroblasts, which are known to display distinct immunogenic profiles, are both potential targets for transgene expression in cutaneous gene therapy. However, whether there is an immunological advantage in targeting one cell type over the other is not known. To study the effect of cell type on transgene-specific host responses independent of antigen levels or methods of gene transfer and transplantation, we used a skin transplantation model in which transgene expression can be targeted transgene to either keratinocytes or fibroblasts. Although targeting an antigen to either cell type resulted in the induction of immune responses, these responses differed significantly. Transgenic keratinocytes were rejected acutely by a dominant Th2 response, while in the majority of grafted animals transgenic fibroblasts failed to induce acute rejection despite the induction of Th1 type inflammation in the graft. In a small number of mice, transgenic fibroblasts persisted for at least 20 weeks despite elicitation of antigen-specific responses. Therefore, fibroblasts may be an immunologically preferred target over keratinocytes for cutaneous gene therapy.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC2741533 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Transgene-specific host responses in cutaneous gene therapy: the role of cells expressing the transgene.

Zhang Z Z Kuscu C C Ghazizadeh S S

Gene therapy 20090514 9

A major issue in long-term gene therapy is host immune responses to therapeutic cells when transgene encodes a potential antigen. The nature of these responses depends on several factors including the type of cell and tissue expressing the transgene. Keratinocytes and fibroblasts, which are known to display distinct immunogenic profiles, are both potential targets for transgene expression in cutaneous gene therapy. However, whether there is an immunological advantage in targeting one cell type o ...[more]

PMID: 19440226

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Project description:Antigen-specific tolerance induction using autologous B-cell gene therapy is a potential treatment to eliminate undesirable immune responses. For example, we have shown that experimental autoimmune encephalomyelitis (EAE) and type 1 diabetes in NOD mice can be ameliorated using antigen-Ig fusion protein transduced B cells. However, it is well established that auto-reactive antigen-specific B cells are activated in many autoimmune diseases and can contribute to pathogenesis. While syngeneic B cells from immunized or autoimmune mice can serve as tolerogenic antigen-presenting cells (APC), this observation begs the question of whether the antigen-specific B cells per se can be transduced as tolerogenic APC. To test this, we employed two model systems employing B cell receptor (BCR) transgenic or wild type (wt) mice as B-cell donors. While adoptively transferred MOG-Ig transduced wt C57Bl/6 B cells were highly tolerogenic and ameliorated EAE, MOG-Ig transduced anti-MOG B cells from BCR transgenic mice were not. This phenomenon was reproduced in the NOD diabetes model in which pro-insulin-Ig transduced polyclonal wt NOD B cells were protective, whereas similarly transduced anti-insulin BCR B cells were not. Since the frequency of antigen-specific B cells in an immunized animal is quite low, we wished to determine the threshold numbers of BCR transgenic B cells that could be present in an effective transduced population. Therefore, we "spiked" polyclonal wt C57Bl/6 B cells with different numbers of anti-MOG BCR transgenic B cells. In the EAE model, we found protection when BCR B cells were present at 1%, but they prevented tolerance induction at 10%. Antigen-specific B cells expressed normal levels of co-stimulatory molecules and were tolerogenic when transduced with an irrelevant antigen (OVA). Thus, the presence of a BCR specific for the target autoantigen may interfere with the tolerogenic process to that antigen, but BCR-specific B cells are not intrinsically defective as tolerogenic APC. Taken together, these data suggest that antigen-specific tolerance induction can be achieved in the presence of a limited number of antigen-specific B cells, but higher numbers of pathogenic B cells may mask this induction. This observation should guide future development of therapies using autologous B cells to treat patients with autoimmune diseases.

Project description:Neural stem cell (NSC) therapy is a promising therapeutic strategy for stroke. Researchers have frequently carried out genetic modification or gene editing of stem cells to improve survival or therapeutic function. However, NSC transplantation carries the risk of immune rejection, and genetic modification or gene-editing might further increase this risk. For instance, recent studies have reported on manipulating the stem cell genome and transplantation via the insertion of an exogenous gene derived from magnetotactic bacteria. However, whether transgene-modified stem cells are capable of inducing immunological reactions has not been explored. Although NSCs rarely express the major histocompatibility complex (MHC), they can still cause some immunological issues. To investigate whether transgene-modified NSCs aggravate immunological responses, we detected the changes in peripheral immune organs and intracerebral astrocytes, glial cells, and MHC-I and MHC-II molecules after the injection of GFP-labeled or mms6-GFP-labeled NSCs in a rat model. Xenogeneic human embryonic kidney (HEK-293T) cells were grafted as a positive control group. Our results indicated that xenogeneic cell transplantation resulted in a strong peripheral splenic response, increased astrocytes, enhanced microglial responses, and upregulation of MHC-I and MHC-II expression on the third day of transplantation. But they decreased obviously except Iba-1 positive cells and MHC-II expression. When injection of both mms6-GFP-labeled NSCs and GFP-labeled NSCs also induced similar responses as HEK-293T cells on the third days, but MHC-I and MHC-II expression decreased 3 weeks after transplantation. In addition, mms6 transgene-modified NSCs did not produce peripheral splenic response responses as well as astrocytes, microglial cells, MHC-I and MHC-II positive cells responses when compared with non-modified NSCs. The present study provides preliminary evidence that transgenic modification does not aggravate immunological responses in NSC transplantation.

Dataset Information

Transgene-specific host responses in cutaneous gene therapy: the role of cells expressing the transgene.

Publications

Transgene-specific host responses in cutaneous gene therapy: the role of cells expressing the transgene.

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