SEGMENT 1: Dr. Monica Kraft discusses her current research into asthma, immune response, and airway remodeling and a future project looking at health disparities.

Dr. Gary H. Gibbons, director, NHLBI:  Hi, I am Gary Gibbons and today my guest is Monica Kraft, a professor of medicine at the Duke University School of Medicine, and director of the Duke Asthma, Allergy, and Airway Center. She is also the immediate past President of the American Thoracic Society.

Monica, again, thank you for taking the time to talk with me today. You are clearly one of the major scientific leaders in academia in the field of asthma research and I look forward to you sharing your thoughts about the state of the field. 

There’s obviously been a long-standing connection between the putative role of the immune system and the natural history of asthma. And I must admit, I have studied the remodeling of blood vessels for much of my career and I was interested that someone has been studying another sort of tubular network, and what you might say about the role of the immune system in shaping airway remodeling in the context of asthma. Tell us a little bit about your most recent research. 

Dr. Monica Kraft, Duke University:  Sure. You know, it started out looking at very, very basic immune mechanisms in asthma. We were just trying to describe what was going on in the human lung, you know, employing techniques like bronchoalveolar lavage and endobronchial biopsies, things like that. We were able to actually look directly in the human lung and then compare and contrast mouse or other animal models of asthma. And then realizing that, you know, the immune system in asthma is quite diverse and that what we thought was more of a T helper 2 interleukin-413 driven inflammation is actually quite simplistic now and that there are a number of different molecular phenotypes that really drive asthma. And it is not all one sort of a homogeneous disease by any means. And I think we are finding this about many chronic diseases.

So I think in the early years, we were really working out allergic mechanisms and how you can modulate that with therapy, the effect of exacerbations in that setting, and how that impacted on long-term structural changes in the airway or what we would call remodeling. And if we could keep inflammation in check, could you impact remodeling?

And I think that may not be entirely true. I think you can have some impact by reducing inflammation but I think there is actually a whole remodeling process that goes on that’s not as responsive to the medications we have now. So hence, the need to really go back up the pathway a little bit farther and look at some of the early life changes that occur and be able to intervene even potentially earlier in life in those patients who are at risk for severe disease or remodeling, and try to intervene early. That would be one path. 

And then I think the field is so… moving into phenotypes, if you will, is very important. And then there is a whole area of host defense and a host response to insults that I think is of equal importance to the adaptive immune response. And that is really what has been taking my time of late, looking at a number of innate immune factors really stemming from the idea that asthma exacerbations are really what lead to – on the airway side – airway injury, dysregulated repair remodeling. But on the clinical side, really significant asthma morbidity, sometimes mortality, a lot of reduction in quality of life. 

So the exacerbation remains a really important aspect of asthma and I don’t feel like we have a very good handle on what are the factors that are dysregulated and what can we do to really intervene to change the course, especially in patients who tend to be more exacerbation prone. So I think if we can understand that a bit better, that whole process a bit better, I think we can really impact on the disease, especially for that important proportion of patients who really do suffer from it. 

Dr. Gibbons:  Very good. And in that regard, with your program, are there specific findings that you have encountered along the way that are particularly surprising or intriguing you right now?

Dr. Kraft:  Yeah, actually. Speaking of the host response and innate immunity, you know, when you move from one institution to another – and I came to Duke nine years ago in 2004 – you know, your science will go in some directions you may not have anticipated. And so one of the areas is looking at surfactant protein A and its role in host defense and the immune response in asthma. And it was really through meeting Jo Rae Wright when I came to Duke and then, of course, continuing, it was interesting, I had already been working with Dennis Voelker at National Jewish [Health], who is a terrific surfactant protein chemist. But yet, it was through the interactions at Duke that really solidified collaborations with Dennis and now we’re all – we were all part of a program project grant. 

Unfortunately, Jo Rae left us too prematurely but we’ve continued on and now looking at why SP-A [surfactant protein A] is dysfunctional in asthma. So it does not perform its usual anti-inflammatory activities. And we actually think it is through potential signaling mechanisms through SHIP-1, sarcomology protein 1. And because that is an important anti-inflammatory arm of the SP-A signaling cascade. And we are in the process of determining if we can design specific peptides that can actually activate SHIP because we’ve also shown that SHIP is dysfunctional in asthma and, therefore, inflammatory insults or infectious insults elicit a much more robust inflammatory response than in normal patients. I mean, over the top and not in the interest of the organism. If we can activate SHIP, we can actually really put the brakes on inflammation in ways we couldn’t before.

So we’re investigating this in animal models right now but some of these ITIM peptides may actually be a novel path for therapy in humans. That’s sort of where we are going with this. Now, this is early. We’re still looking in subculture from patients with asthma and patients without asthma, and looking at animal models. And we’ll see whether these activators can actually enhance the anti-inflammatory response that is missing that is necessary in the setting of infections and inflammation.

So I’m excited about that because that’s really the topic of our program project renewal that we’re working on right now. And we have exciting preliminary data and are putting together some papers. So it’s still early but it’s what’s keeping me, you know, excited and hopeful. It’s all about taking what you learn in the lab and then if you can translate it to care, that’s really the ultimate goal here.

Dr. Gibbons:  So it sounds like there are some promising leads that, as you say, may translate to either novel therapeutics or diagnostics.

Dr. Kraft:  Mm hmm.

Dr. Gibbons:  What else do you sort of see on the horizon in that realm of things that potentially could go from bench to bedside and affect patients?

Dr. Kraft:  Well, there are some very interesting biologics out there in development. Some are very close to approval. Again, really looking at specific inflammatory phenotypes in asthma and then looking at… And I think that’s really the path to go in terms of sorting out which therapies are suited for the right group of patients. Because I think what we’ve done in the past, asthma is similar to other diseases; it’s sort of a one-size-fits-all approach. And now, of course, the buzzwords “personalized” or “precision medicine,” I think we are getting closer to that. I think we’re able to… We’ve got some biomarkers now. We can phenotype patients. We can much better sort out who should receive which therapies. I think we still have a ways to go but I think we’ve come a long way, certainly, since I started in this field. And it’s not all about inhaled steroids anymore. We’ve gotten much more sophisticated about our approach. 

And that’s very exciting, as well, because we’ve shown that not everybody responds equally to inhaled steroids just because asthma is a very heterogeneous disease. So nice to know that we’ve got some other options out there.

Dr. Gibbons:  In a somewhat related sort of vein, as you recognize, a key part of the NHLBI mission, and certainly one of our strategic priorities, is to address health disparities in disorders such as asthma. You alluded to this earlier with the disproportionate burden of the disease in certain communities of color – African Americans and Hispanics, in particular. And as an expert in this area, what do you see as some of the potentially promising opportunities to sort of bend the curve and make an impact on this problem?

Dr. Kraft:  You know, there’s a real interest in this area, and for good reason. It’s been long-standing but now I’m happy to see that more light is being shed on the disparity issues and what are the factors that are really producing these differences. But really, more importantly, what can we do about it?

And so one of the areas is through being involved in a medical society and, of course, the American Thoracic Society is very interested in the topic. And what we can do is really help… What we hope to do is really help shape policy because we have a very big advocacy group. We spend time in Washington on Capitol Hill. We can put forth really important initiatives and write documents and call to arms, etc., to really make sure that the lung community, but also beyond, is aware of these problems. Because I think we want to talk to our government officials and make sure they are aware, because I think programs can be put in place, research dollars can be directed in different ways, depending on governmental policy. And I think a medical society is sort of one way that can help move things in those types of directions, would be one thought.

I think also there are more grant opportunities out there, as well, to really study what types of therapies, what types of interventions really do change these disparities. And I’m actually writing a grant on this topic right now to work with some folks in our Durham community on this. Because we see incredible health disparities in the Durham community in both African Americans and Hispanics/Latinos. And I feel that we would like to use more community-based interventions and tailored adherence tools and greater access to medications and really an understanding of what the barriers to correct care are – provider education, for instance – to really get at the reasons for health outcomes in these populations and then really try to intervene with important tools. And so we’re actually looking at that in our own community at the moment. And regardless of what happens with this grant, we’re planning to pursue this line of investigation because we have some support from the institutions, as well.

So I think more to come on that issue from a local perspective but I think it’s really important; certainly nationally, it’s become a real issue.

Dr. Gibbons:  Okay. That’s wonderful to hear some of the initiatives that you are pursuing.