Prashanth Vallabhajosyula, M.D. M.S., Assistant Professor of Cardiovascular Surgery School of Medicine at the University of Pennsylvania, talks about a new way to save transplant organs using biopsies.
Interview conducted by Ivanhoe Broadcast News in May 2017.
Would you explain to me, how you got the idea for this study, what the study is going to mean to transplant patients eventually?
Dr. Vallabhajosyula: This all started for me initially, when I was working as a post-doctoral fellow in a lab at Massachusetts General Hospital. I was working in a transplant immunology lab and one of the things that came up while I was working in the lab was the constant discussions we had about how, especially in fields like heart and lung transplantation, which is the field that I am in as a surgeon, we really do not have any good way to monitor the transplanted organs in our patients. Currently, most of the clinical monitoring for heart and lung transplant patients is based on biopsies of the transplanted heart or lung. It is estimated that some transplant patients, for example heart transplant patients; can get up to 12 to 15 in biopsies of their transplanted heart in the first two years. We do this because we have no good way to do surveillance in our patients, so my interest in this clinical problem started during my time in the lab as a postdoctoral fellow. So I started digging as to what to do; I was also considering a career in cardiac surgery. At that point as I was doing my research I came across exosomes, they were relatively new in terms of our understanding of their function. Especially very little to no work was done regarding exosomes in transplant patients. People have known about exosomes, in the scientific community, but not as much work had been done. What really attracted me to exosomes was that they are really little packets that are released by many cell types and they carry the set of proteins and nucleic acid molecules inside them that are representative of the cells that are releasing them. What is also exciting about exosomes is that on their surface they can carry the same molecules as the cell that is releasing them. Immediately what came to my mind was that exosomes can be very valuable in transplantation diagnostics. For example, in a heart transplant patient the transplanted heart will release these exosomes into the blood stream of the patient and if there is some way we can pick up those exosomes that belong to the heart, then we may have a noninvasive biomarker instead of having to biopsy these patients. That was when I really started putting things together with this and I really did not get an opportunity to study this until Dr. Naji at my current institution was kind enough to offer me mentorship and some space in his lab, where I could establish an exosomes biology lab. It was all based off of this idea I had in my mind that I was carrying for the six years while I was still completing my clinical training in General Surgery and fellowship in Cardiothoracic Surgery. Things kind of came together and it took us about two years to establish the lab and then get the studies going. Fortunately it turned out that these exosomes seem to be very valuable in terms of their biomarker potential. In collaboration and mentorship under Dr. Naji, what we have shown in animal models and validated the concept in humans is that it turns out these exosomes released by the transplanted organs can be tracked, purified, and characterized; and more importantly, their profiles seem to change very early on in the rejection process, which is very critical from a biomarker standpoint. So what we are hoping this will translate to over time and only time, will tell, is that not only will it be used as platform to supplement or complement biopsy-based techniques, but also to pick up rejection at an earlier stand point to enable timely medical intervention.
You were eluding a second ago about these exosomes kind of talking to each other, can you delve into that a little bit?
Dr. Vallabhajosyula: What we do know is that exosomes seem to play a very important role in communication between cells. It makes sense why cells expend a lot of energy to make and release exosomes. There must be a good reason why they do it, and we think the big reason why is that it is a way for them to communicate with one another: to relay information, to deliver molecules that can change the environment they are in. There is very good evidence for that, in fact, there are studies coming out in the field of transplantation that are starting to suggest the same.
When you do a biopsy, those are invasive, that is like another surgery?
Dr. Vallabhajosyula: It is not as extensive as surgery, but it is invasive and if you think about it from many stand points, if we can have a blood test that can work as a first line of assessment and surveillance and then follow-up with a biopsy if there is any s, it would make a huge difference. Right now patients who undergo heart or lung transplantation have to come to a major tertiary care center typically to get their biopsy. The procedure involves the resources of several health care personnel, and a long time commitment on the part of the patient. Think about what it means to the quality of life for that patient, about the invasiveness of obtaining a small piece of the transplanted heart for analysis, in terms of the cost to our society. All these things hopefully, can be removed one step further if we can get a blood test that is reliable and accurate. And heart biopsies are not trivial, they can cause bleeding into the sac that the heart beats in, and repeated biopsies can cause damage to one of the heart valves.
Let’s just say you take the blood test and you find out, okay it is going to reject, what is the intervention technique or tool at that point?
Dr. Vallabhajosyula: It would be tremendous. First of all to catch rejection very early on would mean a lot to us as physicians, because then we would intervene before there is damage to the organ, which would have a major clinical impact on the patient. In addition, the other important thing is right now in heart and lung transplantation, and in other fields in transplantation as well, we do not have a good way to modulate the medicines we give our patients to block their immune system from rejecting the transplant organ. We throw these immunosuppressive drugs so that the patient’s immune system does not reject the organ, but over long term this is associated with greater risk of infection and cancer in our transplant patients. If there is a simple blood test that can give us a time sensitive window into how the transplanted organ is doing, then it might enable us to adjust patient’s immunosuppression drugs accordingly. This ability could translate to significant improvement in patients’ long-term quality of life and also reduce their risk of contracting infections or developing cancers.
This is an amazing thing, because I think about you guys in the OR performing these transplants, how could you know how much immunosuppressant drugs to administer? That had to be frustrating at the time.
Dr. Vallabhajosyula: I think any progress we can make in this area to improve the lives of our transplant patients would be huge. Especially, as surgeons for us to do the transplants and see our patients and what they go through, it’s quite incredible and inspiring to see their strength. It’s truly one of the greatest joys of my life. And to have an impact where we can actually do something positive for them is tremendous. But it is also frustrating; you are right. You know it is not uncommon for me to do a heart transplant on a patient, and they get a routine biopsy before they are discharged home and from the biopsy they can have some bleeding complication that delays their discharge, or have more adverse clinical effect. These things can and do happen. So if there is some way we can avoid it or delay it without compromising the organ function, it would be tremendous.
With this, how early could you detect it?
Dr. Vallabhajosyula: I can only comment on the animal studies because that is where we have done a robust analysis. The early data in humans look promising, but only time will tell as we hope to carry these ideas to the clinical setting. We now carefully studied this in animal models of islet transplantation, for example, diabetics who need the islets cells, which are responsible for making insulin, the major hormone in our body responsible for regulating our blood sugar levels. In that animal model we noted that well before you start seeing damage to the transplanted islet cells, the exosome signal changes dramatically very early in the process, which is very promising for us from a biomarker standpoint. Hopefully, we will see the same in humans. Further, in the animal studies we noted that changes in the exosome signal predicted rejection with 100% accuracy. We can now characterize the exosome signals. We see them right away; within an hour after transplant we are seeing the exosomes released by these islets in the patient’s blood stream and we are able to reliably track this signal. We now have follow-up in these patients out to five years and at every single time point we can find the exosome signal from the transplanted islets. So from the stand point of its ability to track and detect long term, which is very important for a biomarker, things looks very promising in the clinical setting. We have also now reliably tracked the exosome signal in kidney transplant patients out to a year of follow-up. In fact, in kidney transplant patients we can do the tracking from a urine sample. In animal models, our lab has now found that the idea is true in models of heart and lung transplantation. So we are very excited about the potential of this platform for universal application in transplantation.
When you are actually looking at the exosomes under a microscope, how you see them?
Dr. Vallabhajosyula: These exosomes are very small, they are nanoparticles, so we actually use a special machine called the Nanoparticle Detector. Using that detector, we can actually track these exosomes. And the great thing about this Nanoparticle Detector is that it gives us the ability to look for specific proteins that are expressed on the surface of these exosomes. Using that capability, we can exactly tell from a blood sample what exosomes are released by the transplanted organ; that is what is so very unique about our approach. A lot of groups have looked at exosomes in the blood stream for a marker but they do not find the detailed and specific information I believe our approach can provide. Because what happens is that in our blood we will find exosomes that are released by all organs and tissue types. So when we try to get a read-out of exosomes in our blood as a marker of transplant organ rejection, the read-out gets diluted by exosome signals from other tissues and organs, and it can also create falsely positive results. But if you can somehow specifically get a read-out of the exosomes that belongs to organ of interest, in this case the transplanted organ, then you have something that is very accurate.
How do you do that? How can you confine it to the particular organ?
Dr. Vallabhajosyula: in many ways, that is the entire catch to my idea, is that we found that the very specific proteins on our cells that tell our immune system self from non-self, can be utilized to study the specific exosomes in the blood stream of transplant patients that are released by the transplanted organ. In fact, it is those proteins that are important in the transplant rejection process. That is how the immune system of a patient identifies and attacks the transplanted organ as a foreign body. It turns out that those same proteins are also expressed on exosomes that are released by the transplanted tissue. So we are able to use that specificity for self versus foreign provided by these class of proteins to isolate and profile the exact exosomes that belongs to the transplanted organ.
How excited were you, you did the animal studies and you said human studies are promising, this started with just an idea up in Boston and now look how far down the road you both have come, what is that like for you from a personal and an emotional standpoint?
Dr. Vallabhajosyula: You know the feeling is hard to describe because you have this sense of, “yes, what I thought of very well may be true”, and I say that very well may be because I want to further validate in humans before I can say for sure. With that being said, it is extremely exciting and the most exciting part to me is the feeling that something you have found may actually translate to improving patients’ lives. I am in academic medicine because I want to push the envelope. We love practicing medicine and taking care of patients, but I also want to make it better for them. Then an opportunity like this comes along and you come to realize how grateful you are to even get that chance to have a potential positive impact on your patients. It’s truly a privilege.
Well it is critical to that you are in the OR with a patient and you are going through that entire transplant patient entire process, so you see what kind of impact that it has. That’s got to be in the back of your head, the most important thing that you understand from the patient’s point of view, because you have been in surgery with them?
Dr. Vallabhajosyula: Absolutely, I think that is one of the most wonderful things about being a surgeon scientist, is you get this unique opportunity to be at that interface; being able to ask clinically relevant questions and hopefully have enough of the basic science background and foundation to act on those questions and to address them in scientifically meaningful and rational manner. This fortunately ended up being one of those situations. Besides the sheer joy of practicing surgery, as a surgeon you also get to take this incredible emotional journey with your patients and their respective family members. The whole experience is just amazing.
How far away do you think you think this is from general use in terms of diagnosing early rejection?
Dr. Vallabhajosyula: So, the first set of studies that we did was in an animal model of islet transplantation. We have now extended these studies to animal models of heart and lung transplantation. We are hopefully going to be publishing that data soon. The results in heart transplantation model also look very promising. In humans, we have validated the concept of detection and characterization of transplant organ exosomes in islet transplant and kidney transplant patients. We will be starting work in lung transplant patients as well, in collaboration with the transplant group at Washington University. I really hope that in the next four to five years we can translate this concept into the clinical setting and study it carefully in humans.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Abbey Anderson
Abbey.anderson@uphs.upenn.edu
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here.
