Considering Microglia, T Cells and Bone Marrow Transplants in Rett Syndrome
Today we interview Jonathan Kipnis, PhD, a neuroimmunologist who is looking at how the immune system interacts with the nervous system in Rett Syndrome, and is experimenting with ways to engage that interaction to impact Rett symptoms. The immune system is complex and multifaceted, with inflammatory and anti-inflammatory actions and modulatory influences on various other substances, including neurotrophic factors such as BDNF, familiar to parents who follow Rett research. RSRT is supporting his innovative exploration of bone marrow transplants in Rett models.
MC: Tell us, if you would, a little about your background. I know you trained in Israel.
JK: Yes, I got my BSc, majoring in biology, at Tel Aviv University and then I was off to the Weizmann Institute of Science, which is a wonderful place to do research in Israel. I first worked in the laboratory of Moshe Oren, a very famous cell biologist, and then joined the lab of Michal Schwartz --who was a great mentor for many years-- for my PhD, working on the role of the immune system reactions in CNS injuries. I stayed there for post-doctoral training, and then came to the US. I have been at UVA, the University of Virginia, since 2005 in the Department of Neuroscience, and I’m a member of the Carter Immunology Center, combining my passions for immunology and neuroscience.
MC: So when you decided to go into immunology, were you immediately drawn to neuroimmunology, or did your interest in the brain and CNS come later?
JK: No, no—actually I trained in the Department of Neurobiology, so everyone around me was a neurobiologist except for my mentor, who was trained as an immunologist and then as a neuroscientist, so she definitely inspired my interest and love of both fields. I joined Michal’s lab the year they discovered that T cells, which are a type of lymphocyte, if injected in the right number and at the right time after injury to the brain or the spinal cord, will actually improve the outcome and protect neurons from death.
MC: Do you place them directly into the spinal cord?
JK: No, you don’t have to do that; you just inject them and they find their own way into the spinal cord.
MC: Much in the same way, perhaps, that we hear about embryonic stem cells going to where they’re needed in the brain, for repair?
JK: Absolutely, yes.
Rett Syndrome as a Model
MC: So, how did you get involved with Rett Syndrome?
JK: Okay, so this is quite complicated--- and here is some of the history. To get the benefit of T cells after CNS injury, you need to really boost the number of T cells. The endogenous response is not very efficient. But the unexpected finding was that the spontaneous response is tightly regulated and if it goes out of control, then those same protective cells can become destructive and induce an autoimmune disease. This made us think that maybe endogenous T cell response that barely supports the brain after injury might have a major role in the brain function under physiological conditions. So we did a “crazy” experiment – we took mice that have no adaptive immunity, namely T cells.
MC: These are genetically engineered mice without any T cells?
JK: Yes, they are a model for “bubble kids”. It’s called SCID, severe combined immunodeficiency. They have no lymphocytes. We were very surprised to find that these mice are impaired in many tasks involving learning and memory, and also in brain plasticity. Even more surprising was the fact that when we gave them T cells from wild-type mice by intravenous injection, and checked them again after two weeks, we found they were perfectly fine in their cognitive function! So by aiding immune-deficient mice with T cells we improved their brain function.
MC: That’s very interesting.
JK: Later on, we took wild-type animals as adults and removed their T cells, and saw that their brain function becomes impaired. We still don’t know exactly what the T cells are doing in the brain, although our recent paper suggests that T cells in the brain produce a soluble molecule, called interleukin 4 and through this molecule they regulate the levels of BDNF in the brain. Moreover, T cells regulate synaptogenesis, plasticity and neurogenesis, which have been shown to be impaired in the Rett syndrome.
I started to look at the “immunological” literature of Rett and encountered a wonderful paper from a group at UC Davis----
MC: By Janine LaSalle?
JK: Yes. She showed that in Rett patients there’s a skew in X activation in lymphocytes. That is, they prefer the gene with the normal MECP2. They seem to need it for survival and function.
MC: Do you think that this skewing happens over time?
JK: Perhaps. It would be interesting to see the difference between very young patients and those who are older. My prediction would be that the lymphocyte skewing might increase as they age.
MC: I’ve wondered about that, too.
JK: Obviously there are many important ways that MECP2 affects the neurons, but if the T cells are malfunctioning then that may be part of the picture. So we looked at the Rett male mouse models and found that indeed their T cells are significantly impaired; they do not respond well to what we call the antigenic stimuli. So that was the beginning of our interest, which has continued to grow.
MC: So you were looking for a disease model that could help you with a hypothesis that you had, and Rett Syndrome had all the characteristics that interested you?
MC: As I’m sure you’re aware, there is an MECP2 duplication disorder. It’s seen in boys and those boys often die of infection. In Rett Syndrome we see more subtle issues with infection. It does seem that too much MECP2 causes immune problems. Do you have any thoughts on that?
JK: Well we don’t have in the lab the mouse model for the MECP2 duplication, so we haven’t yet worked with that. But what we do know is that MECP2 as a protein is very important to certain subtypes of T cells that modulate immune response, and those may be malfunctioning in one way in Rett Syndrome, and over-functioning in MECP2 duplication syndrome. At this point it is really pure speculation but I think there may be something there.
MC: There’s nothing in the literature, as you know, but anecdotal information I’ve gathered from families over the past ten years or so includes instances of very, very high white cell counts; stressors that seem to precipitate regression; changed affect in children who seem to do better in some ways during or after a fever. I know of some Rett children who are on IVIG, and although it is for recurrent infections, they also seem to do better neurologically, for instance in terms of movement disorder.
JK: That’s very interesting. There’s so much we don’t know because of the variations in X-inactivation in humans, it’s hard to control for that, and as you say, this really has never been studied properly.
MC: I’ve been hearing quite a bit lately about neuroimmune connections; it seems to be an area of study that is heating up. Can you give us some general history of the field?
JK: The whole field of neuroimmunology was pursued as a sub-field of pathology until the breakthrough discovery that autoreactive T cells could be beneficial. Now many groups are studying the protective function of T cells in different acute and chronic neurodegenerative conditions, such as CNS injury and stroke, Alzheimer’s, Parkinson’s, ALS and many other diseases. All have in common the fact that removal or suppression of T cells results in exacerbation of the disease progression. With our recent work that points to the role of T cells in the healthy brain, we’ve come to understand if you impair immune response you impair normal maintenance of the brain and thus affect cognitive function and probably also other functions of the brain. So what was once viewed as pathology is now being understood as physiology.
MC: How many labs worldwide do you think are working on neuroimmune issues?
JK: Oh, there are dozens and dozens, many working on the deleterious aspects of immune function, like in MS--multiple sclerosis-- and fewer studying the more positive maintenance properties of the immune system. There are four (or even more) journals in the field, and several scientific organizations, such as the ISNI (International Society for Neuroimmunology), the PNIRS (Psychoneuroimmunology Research Society) and others. These meetings attract hundreds (probably over a thousand for the ISNI meeting) of participants.
Bone Marrow Transplant and Rett Syndrome
MC: There was a recent paper by Nobel Laureate Mario Capecchi, fascinating work that caught the attention of quite a few Rett parents, actually. He was able to reverse symptoms of OCD using a bone marrow transplant. Can you talk a little bit about this?
JK: Absolutely. It’s very interesting and it did not surprise us at all. As you know, we have four major types of cells in the brain: the neurons, the astrocytes, oligodendrocytes, and microglia. Microglia are very, very active participants in the brain but are not made in the brain; they come from hematopoietic stem cells in blood or bone marrow. So if you give the mice new bone marrow, after a time the microglia in the brain will be replaced by the new microglia.
As you’re aware, we did something very similar: we took bone marrow from Rett mice and put it into wild-type mice, and our preliminary results show the appearance of Rett symptoms. We are still in the process of characterizing them, but we see signs that plasticity is impaired and we are quantifying motor malfunction as well.
MC: And it’s going to be very interesting, obviously, when you do this the other way around, putting wild-type marrow into Rett mice.
JK: Yes, hopefully we’ll have something to report very soon.
MC: And will you be doing this with newborns? Would it also apply to mature mice?
JK: We will be modulating the immune system in four different ways. I suspect that if we see good effects in newborns, we will see them also in adults.
MC: What can you imagine as the best possible outcome of this work?
JK: Rett is a complex disorder; I am not suggesting it could be entirely cured through the immune components. But we know that these components do affect neurotrophic factors and how the neurons can function, so the hope is that we will see substantial improvement in some aspects of the disease. Rett Syndrome has really captured my attention and we are working as fast as we can to see where this will go.
MC: Thank you very much, and good luck with the experiments. We look forward to giving our readers an update on this novel approach as your work progresses.