Session 9: The Immunology of Organ Transplantation

Transcript of Part 1: Introduction to Transplantation: The Immune Response to Allo- and Xenotransplantation

00:00:14.19	Hi, I'm Megan Sykes.
00:00:16.03	I'm a professor at Columbia University, and I'm the Director of the Columbia Center
00:00:21.10	for Translational Immunology.
00:00:23.17	Today's lecture is an introduction to the field of transplantation, particularly transplantation immunology.
00:00:34.16	Transplantation is inseparable from immunology, because organ transplant rejection
00:00:41.02	and graft-versus-host disease are the result of immune responses caused by genetic differences from...
00:00:48.18	between the transplant donor and the recipient.
00:00:53.14	There are a few definitions I'd like you to understand before I go through my lecture,
00:00:58.20	because I will be using some of these words as I go... go forward.
00:01:02.28	Autologous means an organ or tissue from the self.
00:01:07.19	There are some autologous transplants that are done sometimes,
00:01:11.20	for example pancreatic islets in a person whose pancreas needs to be removed due to pancreatitis.
00:01:17.17	The person will get their islets back so they don't get diabetes.
00:01:23.03	Syngeneic is not from the self, but it's from the next best thing, a genetically identical individual
00:01:29.02	-- an identical twin.
00:01:31.20	In mice, we use syngeneic donors all the time because we have inbred mice --
00:01:39.04	hundreds and thousands of identical twins.
00:01:42.00	In humans, we may have one identical twin in the rare case... in the rare person.
00:01:50.02	Allogeneic is the commonest kind of transplant, that means from another individual,
00:01:54.17	a genetically different individual, of the same species.
00:01:58.13	And that includes anybody who isn't an identical twin: a brother, a sister, a parent.
00:02:04.06	Those are all allogeneic to us.
00:02:06.28	And then finally, xenogeneic.
00:02:08.12	That'll be the topic of my third lecture.
00:02:10.26	A xenogeneic transplant is something that we don't do right now, but we hope to do
00:02:16.10	in the near future.
00:02:17.13	And that involves transplantation from a different species.
00:02:21.21	Okay, well, let's focus for a while on allogeneic organs and tissues.
00:02:27.14	Now, the immune responses that we have to think about when we put an organ
00:02:32.09	from one genetically different individual into another is what we call the host-versus-graft response,
00:02:39.11	the response of the recipient's immune system against the donor, foreign antigens.
00:02:45.25	And T lymphocytes are the main players in this response.
00:02:50.14	Antibodies also happen, and there are specific conditions when antibodies are a concern
00:02:56.00	that I'll talk about later, but many antibody responses are dependent on T cells.
00:03:01.20	And so the T cell can be thought of as a central player in rejection in most instances.
00:03:07.27	Now, in the second part of the slide, I mentioned allogeneic hematopoietic cells.
00:03:15.22	That's what many of you may have heard of as a bone marrow transplant in somebody
00:03:19.22	who has leukemia or lymphoma.
00:03:22.19	That's a commonest reason for doing a hematopoietic cell transplant.
00:03:27.13	It's not always bone marrow.
00:03:28.26	Often, we use mobilized peripheral blood stem cells for a hematopoietic cell transplant.
00:03:35.22	And there, we have to think about immune responses in both directions, because the donor is,
00:03:41.10	again, foreign to the recipient.
00:03:43.16	And again, we have to think about the recipient rejecting the donor.
00:03:47.15	And the main players there are T cells and natural killer cells, and also sometimes antibodies
00:03:53.18	can play a role.
00:03:55.25	But there's another direction we have to think about, because when we do a hematopoietic cell transplant
00:04:01.12	we do things to compromise the recipient's immunity very, very extensively.
00:04:06.10	And then the immune cells that come with the graft can actually attack the recipient.
00:04:12.14	So, it's a donor anti-recipient attack that we call graft-versus-host responses.
00:04:19.03	And T cells and, to some degree, natural killer cells play major roles there.
00:04:25.07	Then, we can think about xenogeneic organs, cells, and tissues.
00:04:30.02	And there, it's mainly the host barrier to the donor that we have to think about,
00:04:35.06	the host-versus-graft response.
00:04:36.09	And it's a very, very strong response involving T cells, natural killer cells, macrophages,
00:04:42.07	and antibodies, even antibodies that aren't T cell dependent.
00:04:45.24	A very strong immune response.
00:04:48.08	Now, there are many ways that we can try to avoid rejection.
00:04:54.02	And I'm speaking now, again, about allogeneic organs, which is the type of organ that
00:04:59.13	we currently transplant.
00:05:00.26	Rarely, we may have an identical twin as a donor.
00:05:04.03	And the very first transplant in humans was done with an identical twin who was able
00:05:09.19	to donate a kidney to his twin brother.
00:05:12.08	Secondly, most... since most people don't have identical twins, we use immunosuppressive drugs.
00:05:19.02	And that really is the standard of care for allowing a graft to be taken without rejection.
00:05:25.14	And finally, I'm going to speak in my second talk about what's sort of
00:05:30.02	the holy grail of transplantation, which is to induce tolerance, immune tolerance.
00:05:34.20	And there have been some recent trials that have actually achieved this in small groups
00:05:39.10	of patients.
00:05:41.05	Now, there's a particular genetic locus that we have to think about when we consider
00:05:47.01	any kind of a transplant.
00:05:48.09	And that's called the HLA, the human leukocyte antigens.
00:05:53.09	Because HLA antigens are extremely polymorphic -- meaning any two individuals who are unrelated
00:06:00.22	are very likely to have completely different HLA genes... and these HLA genes elicit
00:06:08.13	the strongest immune responses by T cells and antibodies.
00:06:13.20	And this slide, here, shows you the importance of HLA matching, that when you have
00:06:23.12	a closely HLA-matched organ -- this is kidney transplantation in a large series --
00:06:31.01	you can see that the rate of graft loss... now, this is following these grafts over 20 years, that there are...
00:06:39.06	is a constant rate of graft loss over time.
00:06:41.20	Grafts... many grafts eventually get rejected.
00:06:44.21	That's called chronic rejection, which I'll come back to.
00:06:47.24	But these lines are a little bit divergent.
00:06:50.07	The ones that are most closely HLA-matched have the longest half-life, the slowest rate of chronic rejection
00:06:57.17	whereas those that are HLA-mismatched more extensively have
00:07:02.24	poorer outcomes over time.
00:07:04.07	So, HLA is important in this regard.
00:07:08.11	Now, what is the cause of rejection.
00:07:11.00	As I mentioned, T cells are central players in the process.
00:07:15.10	Now, acute rejection is... is something that we avoid.
00:07:20.03	We don't like to lose the organ -- ever -- completely.
00:07:23.24	And that's why we use these immunosuppressive drugs.
00:07:26.12	And if we have an episode of rejection, we can usually control it by
00:07:30.17	adding more immunosuppression temporarily.
00:07:33.16	But as I mentioned, these drugs must be taken chronically.
00:07:38.16	And... otherwise, the graft will almost certainly be rejected.
00:07:43.00	Now, I mentioned chronic rejection as a cause of late graft loss in the slide that
00:07:49.05	I just showed you.
00:07:50.14	Unfortunately, that is an ongoing problem in the field.
00:07:53.25	It hasn't been improved by the improvements that we've made in immunosuppressive therapies
00:08:00.14	in the last few decades.
00:08:02.04	So, that is one reason why tolerance is sort of the holy grail in transplantation,
00:08:07.27	because tolerance would mean the immune system treats the donor as self, and chronic rejection
00:08:13.10	wouldn't happen either.
00:08:15.10	Alright.
00:08:16.10	Now, I've talked about rejection as if it's one thing.
00:08:21.10	But in fact there are several different types of graft rejection.
00:08:25.17	One is caused by pre-existing antibodies.
00:08:30.14	And we call that hyperacute rejection.
00:08:32.15	I'll say more about that.
00:08:34.15	Another kind of antibody-mediated rejection is called acute vascular rejection.
00:08:39.23	And that's when antibodies come... get formed after the transplant, but can cause
00:08:45.00	a fairly rapid rejection once they get formed, whereas hyperacute rejection is caused by antibodies
00:08:51.06	that are there before the transplant.
00:08:53.23	Now, the cellular rejection is one that is mediated, caused, by T cells alone,
00:09:00.24	with no antibody role.
00:09:02.12	But as I mentioned, antibodies also depend on T cells for their formation,
00:09:07.05	so some of this acute vascular rejection is antibody... is T cell-dependent.
00:09:13.06	And then chronic rejection, also, is thought to be dependent on T cells, even though
00:09:18.19	there's fairly good evidence that antibodies also play a role.
00:09:22.24	Okay.
00:09:23.24	Now, the first and second types of rejection -- hyperacute and acute vascular --
00:09:28.10	we really try very hard to avoid by selecting our donors and recipients, and in some cases doing
00:09:34.15	special preparation of our recipient, if we think they're at high risk of this.
00:09:39.00	So, let's talk a little bit about hyperacute rejection.
00:09:42.09	Hyperacute rejection can occur in a couple of circumstances.
00:09:46.26	One is if we have blood group-mismatched donors, for example if the recipient is blood group B
00:09:52.27	and the donor is blood group A.
00:09:56.01	The recipient has anti-A antibodies in the... in their serum.
00:09:59.28	And that antibody will immediately bind to the blood vessels of the kidney.
00:10:06.08	As soon as the graft is hooked up, it'll bind to the endothelial cells lining the blood vessels.
00:10:13.07	And what that does is it fixes complement, initiates a whole cascade of inflammatory events
00:10:19.22	that ultimately will activate the coagulation cascade and occlude the blood vessels.
00:10:26.08	So, that graft is lost very, very quickly.
00:10:29.19	And the same thing can happen in... even in a blood group-matched situation, but in which
00:10:35.22	the recipient has made antibodies against donor HLA antigens prior to the transplant.
00:10:43.04	And this can happen because of a prior pregnancy, a prior transplant, or due to blood transfusions
00:10:49.22	that the recipient may have had.
00:10:51.18	And it's exactly the same process.
00:10:53.24	The antibodies in the patient circulation bind to the endothelial cells and fix complement
00:11:01.09	and initiate that same coagulation cascade and occlude the blood vessels of the graft.
00:11:07.04	So, as I just said, it can... hyperacute rejection can occur in blood group-mismatched and presensitized
00:11:14.18	recipients.
00:11:16.25	And on the bottom, it says that hyperacute rejection has presented a barrier to xenotransplantation.
00:11:24.27	As I'll discuss in the xenotransplantation lecture, we've found a way of avoiding that.
00:11:31.09	But it was a major limitation to the field of xenotransplantation over the years.
00:11:36.15	Now, just to show you what hyperacute rejection looks like, this is an experimental study
00:11:42.02	where a rat heart was put into a mouse that had lots of natural antibody against that rat.
00:11:51.20	That's the one on the right, here.
00:11:53.07	And you can see that that heart looks black.
00:11:56.04	And that's because that occlusion of the blood vessels has happened in that very short period of time
00:12:01.22	since the graft was put in.
00:12:03.21	This is half an hour after the transplant.
00:12:06.10	Over here, you see a pink looking graft, and that's a much more normal looking graft.
00:12:12.09	And that's because this mouse that got the rat heart didn't have those high levels of
00:12:16.21	preformed antibody against the rat xenograft.
00:12:20.11	It's a xenograft because it's from one species to another.
00:12:25.07	Okay.
00:12:26.07	Now, acute cellular rejection is a major problem.
00:12:33.00	And it's a common cause of what we call rejection episodes.
00:12:37.25	And we think that this whole process, which... in which, again, the T cell is the central player,
00:12:44.05	gets initiated in part because of procedures that involve... are involved in
00:12:51.02	obtaining an organ from a donor, transplanting it to the recipient.
00:12:55.22	And there's a period where there's no blood flow to that graft, called ischemia.
00:13:01.00	And that ischemia can activate all sorts of components of the innate immune system.
00:13:07.13	And the innate immune system is very effective at activating T cells.
00:13:12.16	And it's actually T cells, as I mentioned, that are the real players in this graft rejection.
00:13:19.03	And the strongest rejections are directed against those HLA differences that I mentioned,
00:13:25.10	but also what's called minor histocompatibility antigens, which are basically peptides
00:13:31.03	that are presented by an HLA antigen, but they're peptides of proteins that have some polymorphism,
00:13:37.28	and may differ between the donor and recipient.
00:13:40.21	We have many such polymorphisms.
00:13:43.26	And so, even in the setting of HLA matching, there are many minor histocompatibility antigens
00:13:49.17	that can be presented and cause a T cell-mediated rejection.
00:13:54.15	And this is if you had a really bad T cell-mediated rejection that destroyed the graft,
00:13:59.27	this is what it would look like.
00:14:00.27	It's... it's quite swollen, and it's white.
00:14:03.04	And it's white because of all the leukocytes, the white cells, the lymphocytes, etc,
00:14:08.19	that are infiltrating the graft.
00:14:12.01	As I mentioned, it's a T cell-mediated process.
00:14:15.04	This stain here is an immunostain for... with anti-CD3.
00:14:18.19	And you can see there's a lot of those T cells that express CD3 in the graft.
00:14:25.03	And histologically, you can just see this gross infiltrate of cells with blue nuclei
00:14:30.28	and very little cytoplasm.
00:14:32.11	Those are largely lymphocytes.
00:14:35.02	Okay.
00:14:36.09	Well, what causes this T cell response?
00:14:41.00	There are two types of T cell responses.
00:14:44.10	One is called direct allorecognition, and the other is called indirect allorecognition,
00:14:50.23	in transplantation.
00:14:52.19	And indirect allorecognition is actually like... a lot like any other type of immune response.
00:14:58.04	And I'll tell you why in a minute.
00:15:00.25	Direct allorecognition is quite unique -- it's different from most immune responses --
00:15:06.19	because it actually is seeing the allogeneic HLA presenting a peptide.
00:15:14.17	And there are many, many such possible allogeneic HLA/peptide complexes on a donor graft.
00:15:23.23	And this elicits a very strong response.
00:15:25.26	And we have both CD4 and CD8 T cells that can recognize this donor.
00:15:32.13	And the essential point of direct allorecognition is that it's directly recognizing antigen
00:15:38.26	presented by a donor cell.
00:15:40.22	So, this is a donor dendritic cell, an antigen-presenting cell that is presenting these donor HLA molecules.
00:15:49.24	And that... that's the direct response.
00:15:52.24	Indirect allorecognition is a little bit different, because it in fact involves a recipient antigen-presenting...
00:16:01.11	presenting cell, here, a recipient dendritic cell.
00:16:04.06	And what happens is that recipient antigen-presenting cell picks up donor antigens,
00:16:09.28	such as these HLA molecules, internalizes them,
00:16:14.27	processes them through the antigen processing pathway,
00:16:18.04	and re-presents them on a recipient MHC molecule, a class II molecule, that is on the surface
00:16:25.13	of the recipient dendritic cell.
00:16:27.12	So, this recipient CD4 T cell, in this slide, is actually recognizing a donor HLA-derived peptide
00:16:36.13	presented by a recipient HLA molecule on a recipient antigen-presenting cell.
00:16:43.02	Alright.
00:16:44.03	Well, HLA differences between donors and recipients activate a very large number of T cells
00:16:51.11	of different specificities.
00:16:53.10	And this results in the response to HLA
00:16:56.23	-- which is the human form of the major histocompatibility complex, the MHC --
00:17:02.22	being stronger than any ordinary immune response.
00:17:07.08	So, this is an extraordinary response.
00:17:09.17	Now, the reason for this is that T cell receptors are... have evolved to recognize MHC/peptide.
00:17:18.05	And so there's this inherent fit between T cell receptors and MHC/peptide complexes.
00:17:25.01	And T cells get positively selected in the thymus to weakly recognize a self MHC/peptide complex.
00:17:32.15	But what happens, in order to avoid autoimmunity, is that they undergo this other process
00:17:38.02	called negative selection, in the thymus, that weeds out the T cells that strongly recognize
00:17:43.15	self MHC/peptide complexes.
00:17:46.09	But there's no donor cells in that... in your thymus that contribute to that process,
00:17:51.13	so you don't weed out T cells that recognize alloantigens.
00:17:55.16	So, this combination of inherent MHC recognition, and not being weeded out for the donor,
00:18:03.01	results in a lot of T cells that see the donor.
00:18:06.06	And one of the results of this is that we can actually measure responses
00:18:10.26	to an allogeneic HLA-mismatched donor just in cells that we take right out of a person.
00:18:17.03	We don't have to give any immunization to see this.
00:18:20.23	And these two responses, called the mixed lymphocyte reaction, in which we measure
00:18:27.17	either T cell proliferation or cytotoxic T cell activity against the donor cells,
00:18:35.13	are our measures of this very strong response.
00:18:39.15	You don't see that for other types of immune responses.
00:18:42.27	You have to immunize.
00:18:44.05	And in fact, it's been estimated that anywhere from about 1-10% of T cells will recognize
00:18:52.16	a given MHC-mismatched allogeneic donor, which is a huge, huge proportion of this
00:19:00.19	very diverse T cell repertoire that we have.
00:19:03.25	I've been talking mainly about acute rejection up until now.
00:19:07.15	And chronic rejection is another type of rejection that is much more slow than acute rejection.
00:19:15.24	And we've made pretty good inroads into reducing acute rejection and graft loss rates
00:19:21.07	with modern immunosuppression.
00:19:23.10	But we haven't done much to eliminate this slower form of rejection, that we call chronic rejection.
00:19:30.12	And the mechanisms of chronic rejection are not fully understood.
00:19:34.20	They may involve, probably, some of the same processes that I've referred to.
00:19:39.17	But it's thought that indirect recognition plays a major role, mainly because the antigen-presenting cells,
00:19:45.20	the professional APCs that come with the graft,
00:19:49.09	do get replaced over time by the recipient's.
00:19:53.00	So, you have more recipient APCs around to present antigen.
00:19:56.10	And indirect recognition is very effective at inducing antibody responses.
00:20:01.14	And antibodies may play a very important role in many instances of chronic rejection.
00:20:09.09	Now, the reason for that is that the B cells are particularly focused on alloantigens.
00:20:20.23	Because... here's an example of a B cell that has a receptor, a surface immunoglobulin receptor,
00:20:29.03	that recognizes an allogeneic donor HLA class I molecule.
00:20:34.08	And what happens is that B cell, by recognizing that molecule, will selectively pick it up
00:20:41.12	and process it, and present it through its class II molecule to a CD4 cell, shown here.
00:20:50.09	So, that CD4 cell helps that B cell, which has focused its antigen... its peptide antigen that
00:20:57.04	that CD4 cell recognizes, and helps the B cell.
00:21:01.26	So, it's a T cell/B cell interaction.
00:21:04.25	Over here, you have the dendritic cell that initially primed that CD4 cell, but that CD4
00:21:11.02	now can very effectively induce antibody responses by that particular B cell.
00:21:17.00	So, that's the indirect pathway of inducing alloantibody responses.
00:21:22.10	Now, there's a third pathway of allorecognition that's only been recognized in the...
00:21:27.26	in the last few years, and that's called semidirect allorecognition.
00:21:32.12	And what that means is... it... it's still a recipient dendritic cell, a recipient antigen-presenting cell
00:21:41.06	that is presenting antigen to the T cell.
00:21:44.16	But instead of picking up and processing antigen, as we saw for the indirect pathway, over here,
00:21:53.22	what happens is that recipient antigen-presenting cell actually steals entire MHC/peptide complexes
00:22:04.02	away from the donor cell.
00:22:05.19	It picks it up in intact form from the cell membrane, and presents it on its own cell membrane.
00:22:13.15	Some people refer to it as crossdressing.
00:22:15.27	It's the recipient dendritic cell looking like the donor in terms of the HLA/peptide complexes
00:22:23.02	that it presents.
00:22:24.26	And that's important because we know we have donor HLA around as long as we have
00:22:29.20	a donor graft around.
00:22:31.23	And it means that... since the T cells that recognize these donor HLA/peptide complexes
00:22:38.22	are the ones that we originally described as directly alloreactive, it means those cells,
00:22:44.01	which are so abundant, have a constant trigger through this pathway.
00:22:49.19	Okay, how do we prevent all this?
00:22:52.16	I mentioned that lifelong immunosuppressive drugs are the standard of care.
00:22:57.00	That's how we get organs to be accepted for many years in many people.
00:23:02.20	And there are several types of drugs that we use in combination.
00:23:07.27	Steroids are not on this list, but corticosteroids that have very broad effects on
00:23:14.10	the immune system are commonly used as one of three drugs.
00:23:18.25	The second drug is often a cytotoxic drug, such as azathioprine or, more recently, mycophenolate mofetil.
00:23:27.11	And what these [drugs] do is they specifically target proliferating T cells...
00:23:33.02	proliferating cells, like T cells and B cells.
00:23:37.09	And then finally, the third drug is often a calcineurin inhibitor, like cyclosporine
00:23:42.07	or tacrolimus or, instead, rapamycin,
00:23:47.00	all of which are very selective for targeting T cell activation.
00:23:54.08	And rapamycin is a little bit different in its mechanism of action compared to
00:23:59.06	the calcineurin inhibitors.
00:24:02.11	Rapamycin actually inhibits the mammalian target of rapamycin, which is a different pathway,
00:24:08.26	pand may have advantages in sparing a regulatory subset of T cells when it's blocked.
00:24:17.20	Okay.
00:24:18.20	So, that's organ transplantation, rejection, how we prevent rejection.
00:24:23.02	I'm now going to end with just a few slides about hematopoietic cell transplantation,
00:24:28.24	which I mentioned early on.
00:24:30.28	Hematopoietic cell transplantation can involve bone marrow, which used to be the usual type
00:24:37.16	of transplant.
00:24:39.06	But more recently, a lot of people get mobilized peripheral blood instead.
00:24:44.10	And what that involves is treating the donor with a drug, GCSF, or there are some
00:24:50.28	more recent drugs, that actually cause the bone marrow stem cells to leave their home
00:24:55.09	in the bone marrow and go into the circulation.
00:24:58.06	And so now you can just, using a leukapheresis catheter, collect peripheral blood that is
00:25:04.04	very enriched for the bone marrow stem cells that we need for our transplant.
00:25:10.10	Cord blood is another source of hematopoietic cell transplants.
00:25:14.21	And finally, we can actually enrich the hematopoietic stem cells from any of these tissues.
00:25:20.22	CD34 is a marker that is on stem cells, as well as a variety of other cells,
00:25:26.24	and often CD34 selection is used to enrich the stem cells.
00:25:30.25	And the main application of bone marrow... of hematopoietic cell transplantation is
00:25:36.22	in the treatment of hematologic malignancies, like leukemias and lymphomas,
00:25:43.02	but also in treating genetic diseases of blood forming cells, immunodeficiency disease and
00:25:48.15	sickle cell disease, etc.
00:25:50.23	Okay.
00:25:51.23	Well, as I mentioned at the beginning, we have an issue.
00:25:56.00	In addition to the recipient rejecting the donor, we have the issue of graft-versus-host disease
00:26:01.17	when we do hematopoietic cell transplants.
00:26:04.17	And that's in a sense the donor rejecting the recipient, the donor attacking the recipient.
00:26:10.11	And that is also -- just like rejection -- dependent on T cells.
00:26:14.03	They're the key players.
00:26:15.24	And what happens is donor T cells seeing foreign antigens in the heavily compromised recipient
00:26:22.13	get activated, and they attack cells of the... of the epithelium... of the epithelial tissues,
00:26:29.00	skin, anywhere in the intestine... in the intestinal system, and liver are
00:26:34.01	the main targets.
00:26:35.11	And there are acute and chronic forms, just like rejection.
00:26:39.28	And through most of the clinical field of hematopoietic cell transplantation,
00:26:45.20	graft-versus-host disease has been such a big problem when HLA barriers are crossed
00:26:51.07	that it has been necessary to find an HLA-matched donor.
00:26:56.10	And of course that could be a sibling, because we all have two different HLA loci.
00:27:03.03	With any given sibling who's not an identical twin, there's a 1-in-4 chance that there will be
00:27:08.28	a complete HLA match at both loci, at both alleles.
00:27:17.04	Now, that obviously is only 25% of people who are lucky enough to have an HLA-identical sibling,
00:27:23.02	and so this has led to the development of large bone marrow transplant registries,
00:27:28.01	where people have volunteered to be HLA-typed, and then to give their hematopoietic cells
00:27:32.21	to somebody who may need a transplant who they don't know and are unrelated to.
00:27:37.14	But that takes millions and millions of people, because of the extensive polymorphism of HLA.
00:27:43.28	Finding a matched donor is like finding a needle in the haystack, but it's done.
00:27:49.02	Now, recently, the field has advanced so that we are able to perform
00:27:54.11	more extensively mismatched transplants, HLA-mismatched transplants.
00:27:58.16	And this is getting more and more common at multiple centers.
00:28:03.24	Okay.
00:28:04.24	So, what is this whole graft-versus-host disease?
00:28:07.06	How does this happen?
00:28:09.00	So, what happens is we give our allogeneic bone marrow transplant, for example,
00:28:16.13	and that contains mature T cells, okay?
00:28:20.00	Those T cells get infused with the graft, you know, through the vein.
00:28:24.12	And they come in, and they go into the recipient lymphoid structures, like the lymph node
00:28:29.12	and the spleen.
00:28:30.12	And they actually get trapped there, because those structures are so full of recipient
00:28:35.07	antigen-presenting cells.
00:28:36.07	So, over a period of several days, those donor T cells recognizing recipient antigens
00:28:42.07	on these recipient APCs will get activated and expand.
00:28:46.16	And then they will... they will leave the lymph node and go back into the circulation.
00:28:52.11	And if the recipient has been treated with a conditioning that causes inflammation
00:29:00.10	in those epithelial target tissues -- and conditioning being irradiation, chemotherapy, etc --
00:29:07.19	those tissues themselves are inflamed.
00:29:10.25	And those tissues will provide signals that allow those activated T cells that get in
00:29:17.03	the circulation to enter those epithelial tissues and cause this disease called
00:29:22.19	graft-versus-host disease.
00:29:24.13	Okay.
00:29:25.13	Well, how can we prevent it?
00:29:26.25	The obvious one is to deplete the T cells from the donor graft.
00:29:31.28	And that works.
00:29:33.02	But it has some caveats.
00:29:35.17	First of all, it turns out that those donor T cells help the bone marrow to engraft,
00:29:41.14	to overcome the recipient rejection of the donor.
00:29:43.17	And there is an increase in rejection if we T cell deplete our donors.
00:29:48.09	Secondly, most of these... many of these transplants are done to treat malignant diseases.
00:29:55.00	And it turns out that the T cells in the donor graft are a kind of immunotherapy.
00:30:00.11	They actually kill off residual leukemia or lymphoma cells in the recipient that
00:30:07.20	didn't get killed by the chemo or radiotherapy.
00:30:10.26	And so there are higher relapse rates when we T cell deplete our donor grafts;
00:30:15.11	we take away that immunotherapy.
00:30:18.15	And thirdly, adults have a very hard time reconstituting their immune systems
00:30:24.10	after they've had all this treatment.
00:30:26.04	And if you T cell deplete your donor graft, you are more... the recipient is more prone
00:30:32.05	to serious infections.
00:30:33.23	There's quite a long period of immunodeficiency before the immune system recovers.
00:30:38.09	So, donor T cells also have the risk of anti-infectious immunity.
00:30:45.00	Okay.
00:30:46.00	So, I mentioned that relapse rates are higher when we T cell deplete the donor.
00:30:50.18	And that's because that alloreactivity against the recipient, while it's harmful and
00:30:56.04	causes graft-versus-host disease, it also attacks residual malignant cells in the recipient.
00:31:01.00	And natural killer cells, at least with certain types of malignancies, also have the ability
00:31:06.24	to attack malignant cells.
00:31:09.07	And so they can also be beneficial.
00:31:11.22	And then there are a variety of other strategies people are looking at.
00:31:17.11	Differences... changing immunosuppression, and many, many forms of immunomodulation
00:31:24.25	that are being explored to reduce graft-versus-host disease.
00:31:28.09	And the holy grail is to try and preserve antitumor reactivity in this case.
00:31:35.17	And this can be done in ways that... for example, controlling the trafficking of T cells
00:31:41.13	so you can still use the alloreactivity within the lymphohematopoietic system to give you
00:31:46.23	an anti-leukemia effect.
00:31:49.10	Or many groups are working on specifically targeting tumor antigens with a variety of
00:31:56.07	approaches.
00:31:57.07	So, that's the end of the first presentation.
00:31:59.11	Thank you for your attention.