Conclusions and Proposals for Future Work

Within the past 10-15 years, research in the field of AA has been fairly successful in uncovering a molecular basis as well as useful treatments for AA. Much of this can be considered a result of a meeting between major researchers in the field that sought to consolidate information on AA and develop new areas for research. In this meeting, researchers not only spoke of their own research, but worked together to create a comprehensive analysis of all FDA approved drugs to treat autoimmune diseases (Hordinsky 2011). Because of this, researchers then wanted to elucidate more specific drug targets by investigating the mechanism of AA pathogenesis. A number of papers have been published that lead to Xing et. al.’s use of tofactinib and ruxolitinib to target Janus Tyrosine Kinases (JAKs) and reverse the effects of AA. For example, Xing et. al. would have been able to release their comprehensive study without information from the genome-wide association study (Petukhova 2010) or without information on IFN-γ’s role in conferring AA (Freyschmidt-Paul 2006). While these results seem very promising, the field has moved forward and researchers have identified other drug targets besides JAKs. Even though targets have been identified, researchers have yet to develop the small molecule drugs to inhibit these other targets.

Firstly, more studies should be conducted using ruxolitinib since it is a newly developed off-label treatment for AA. The results were astounding in that the patients treated with ruxolitinib were able to regrow nearly 100% of their hair (Xing 2014). The biggest problem here is that ruxolitinib is an FDA approved drug that treats high-risk myelofibrosis (Bertolini 2014). It would be beneficial to run tests that look to investigate the effects of inhibiting JAKs in AA afflicted, but otherwise healthy patients. Since the Janus family of tyrosine kinases are widely used in the body as a means of stress-signaling, inhibiting them may cause unwanted side effects that may pertain to arthritis or myelofibrosis. There likely hasn’t been much research on what treating a healthy individual with ruxolitinib could do because it had previously only been prescribed to those already suffering from myelofibrosis. This kind of research would have served no purpose when developing ruxolitinib to treat myelofibrosis. The ideal experiment would be run in C3H/HeJ model mice before clinical trials with ruxolitinib should move forward. Despite the authors using ruxolitinib successfully to treat AA, there was no mention of any long-term effects or a patient’s propensity to relapse. All of these must be taken into consideration before the FDA can approve this medication for AA.

Since it is never wise to put all of your eggs in one basket, there should still be a concerted effort to continue the development of new drugs, as there are plenty of other avenues of treatment for AA. This is largely due to researchers uncovering the details of the positive feedback loop that leads to the overproduction of CD8+ T cells around the anagen hair follicle. One method of blocking this positive feedback loop may be to develop a method of blocking antigen presentation on the CD8+ T cell or blocking the costimulatory action of CD4+ T cells (Hordinsky 2004). For example, there are proteins whose functions are to act as the on and off switch for the immune system. To suppress an immune response, CTLA4 must be stimulated so it can transmit that message to other T cells. Developing a drug that can act to suppress an immune response locally might be the best option for drug development. It would not be wise to entirely suppress the immune system, as it would leave the patient open to bacterial or viral infection. A better option, which has been a widely used strategy in AA treatment, would be to develop this drug to have a topical or interlesional application to ensure site specific action.

Figure 1: Structure of CTLA4. (Source: Yu et. al. 2011)
Figure 1: Structure of CTLA4. (Source: Yu et. al. 2011)

A third, and final, proposal for future work might be to look into the effects that vitamin D might have on suppressing or controlling the immune response. Vitamin D has been implicated as an important part of the immune system in recent research. Its proposed function is to bind to vitamin D receptors (VDRs) in cells that dimerize and act as transcription factors to influence the production of anti-microbial peptides.

Figure 2: Bioactive Vitamin D3 inhibits antigen presentation to CD4+ (helper) T cells. (Source: persona image)
Figure 2: Bioactive Vitamin D3 inhibits antigen presentation to CD4+ (helper) T cells. (Source: persona image)

 

Another function that vitamin D promotes is the suppression of  T helper cells, or CD4+ T cells which are known to have a co-stimulatory effect on AA pathogenesis (see figure 2, above). In the presence of vitamin D, antigen presentation to CD4+ cells is inhibited and therefore cannot continue to propagate in response the antigen (Hordinsky 2011). This would greatly reduce the proliferation of CD8+ T cells that accumulate near the bottom of the hair follicle and prevent hair growth. This could be used in conjunction with other medication if the response is not strong enough. Overall, AA research has been progressing at a fairly quick pace. Future research should help to further elucidate the mechanism of AA as well as continue to investigate creative and useful ways to suppress CD8+ T cell proliferation and the positive feedback loop in AA.

 

More on Alopecia:

History and Metabolic Context

Molecular Basis

Treatment

Annotated Bibliography

2 Replies to “Conclusions and Proposals for Future Work”

  1. Hello again Sir Matthew,

    All of your pages rock. If I could just give another quick tip, I wouldn’t end the discussion of this page with a figure. I know you discuss it in the paragraph before hand, but maybe break up that paragraph and put it in the middle or something? That part is up to you, but I wouldn’t end with it. Also, like I said, you discuss it very well, but try to reference the figures by saying something like…. ‘blah blah blah, as seen in Figure ___ below. Blah blah blah…’

    1. Good evening Sir,
      I am changing the location of the last figure. Thanks for the input 😀

Comments are closed.