The final manuscript has now been posted on Dropbox as well.
Organ transplantation has the ability to extend the life-expectancy of many patients with severe illnesses. However, if the Human Leukocyte Antigens (HLA) of the donor and recipient do not match almost exactly, the recipient’s own immune system can jeopardize the health of the transplant. While the immune system is extremely complex, several immunosuppressant drugs have been developed that inhibit this negative response [1]. As many of these drugs target T-cell proliferation in general, this results in a greatly reduced ability to respond to infections. Targeting only a specific step in the immune pathway would allow for the continuation of many other aspects of the immune response and decrease the likelihood of acquiring an opportunistic infection.
Figure 1. There are many steps in the immune system pathway. Inhibiting something specific, such a cytokine, could lessen the intensity of the response.
Interferon-gamma (IFN-γ) is a 16 kDa cytokine that is 143 amino acids in length [2]. It is released when T-cells are stimulated by Interleukin-18 and has been found to induce expression of HLA-DR (a major histocompatibility complex cell surface receptor) which in turn mediates graft-versus-host disease. This is due to non-matching HLA’s and ultimately contributes to transplant rejection [3]. To decrease the levels of IFN-γ without entirely inhibiting its production, an aptamer could be developed to specifically bind to the cytokine. This would change its formation and prevent it from interacting with its receptor (CXCR3), reducing the amount of signals that would continue along the immune response pathway.
Figure 2: Interleukin 18 stimulates T-cells to release IFN-γ. The aptamer would then bind to the cytokine and change its shape, rendering it unable to bind to its receptors (CXCR3).
Many experiments have been performed involving the inhibition of IFN-γ and its relation to transplant rejection. For instance, Skurkovich B. et. al determined that treatment with anti-interferon gamma antibodies improved corneal transplant rejection [3]. While most of the other inhibiting agents were also antibodies; one paper (Lee et. al) did describe an oligonucleotide sequence that was determined to inhibit the interaction between IFN-γ and its receptor [4]. This proposal plans to select an aptamer instead of using antibodies due to the high level of specificity necessary as there are several different types of Interferon.
Genway Bio: 50 µg $165 (IFN-γ with His tag) Catalogue Number: 10-663-45807
[1] Duncan and Wilkes. “Transplant-related Immunosuppression, A Review of Immunosuppression and Pulmonary Infections”. The Proceedings of the American Thoracic Society. 2005; 2:449-455
[2] Horst Ibelgaufts' COPE: Cytokines & Cells Online Pathfinder Encyclopaedia. http://www.copewith cytokines.de/cope.cgi?key=IFN-gamma
[3] Skurkovich B. “Treatment of corneal transplant rejection in humans with anti-interferon-gamma antibodies”. Am J Ophthalmol. 2002; 133(6):829-30.
[4] Lee et. al. “An oligonucleotide blocks interferon-gamma signal transduction”. Transplantation. 1996; 62(9):1297-301.
Figure 1: figure taken from medscape.com “Transplantation Tolerance”. http://cme.medscape.com/ viewarticle/418534_3 .
6 comments:
This is a great idea, Ashley! Such an aptamer could be momentous, especially with the development of stem cell organs. You stated that "targeting only a specific step in the immune pathway would allow for the continuation of many other aspects of the immune response and decrease the likelihood of acquiring an opportunistic infection." Although I understand the aptamer would not be one hundred percent efficient, have there been any cases where blocking one step, in this case the HLN-AR release by IFN, completely disrupted the immune response, deeming the action more harmful than beneficial?
Thanks Alec-
I did read a couple papers where the subject (a rat or a mouse)was found to be more susceptible to infection. It was unclear (or I can't remember correctly) whether or not the entire immune response was disrupted but that is a definite concern.
Good abstract!
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Could this have any negative effect in immune response in the long run?
You mention other experiments, how is this better/worse?
Ashely, great idea! You mention an "oligonucleotide" against INF-g, but do not go into more detail. Could you provide a sentence or two about this oligonucleotide? What is it, how does it work, is it an aptamer or an siRNA? How would your aptamer be different?
As for the target, I purchased it from Genway. Good job providing information. Here is the link to the target, Cat# 10-663-45807
Great Job Ashley!
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