Transplants el pt

GVHD: Graft versus Host Disease

Date: July 27, 2024

by Chaya Venkat

Controlling This Killer Is the Holy Grail of Transplants

Stem cell transplant procedures are improving day by day. We are getting pretty good at matching donors with patients, reducing sharply the number of patients who fail to engraft because the graft got kicked out as “unacceptable” by the body. There was a time when the matching was made on 4 points - then it became 6, then 8, and now the HLA matching is made on a 10 point scale. At present a 10 point match is as good as it gets (Matching Made Simple). With better matching, the major handicap of unrelated donors has gone away. In fact, as we discussed in a previous article (The Only Real Cure Out There), MUD (matched unrelated donor) transplants are getting significantly better responses than related donor transplants. Another area where big improvements are being made is in the conditioning regimen used to prep the patient prior to the actual transplant. Full-blown, heavy duty myeloablative transplants are giving way to “kinder and gentler” mini-transplants, using lower doses of chemotherapy and radiation and therefore with significant reduction in toxicity.

But one area that is still of concern is the high level of misery and even death associated with GVHD, where the new graft starts attacking different parts of your body, a case of an immune system gone amok. In this article I will try to give you a little insight into what makes the graft tick, some of the things that may help control deadly GVHD. This information is important to you even if you are not in the market for a transplant, many of the issues dealt with here are also relevant to protecting the mucosal barrier of your gut, mouth and airways. You would be surprised how many life threatening infections get their start because of breakdown of mucosal barrier.

The New Broom Has to Start Sweeping Right Away

Mini-stem cell transplants depend on the donor’s immune system to take over the job that your own immune system flunked. Here is a thumbnail sketch of what should happen immediately after you get the graft from your donor of choice:

• The donor’s stem cells gradually find their way to the recently vacated bone marrow, and once they are comfortably settled in their new home it is hoped they will begin making perfectly good platelets, red blood cells, neutrophils and other cell lines needed for a long and healthy life. This typically takes a little while, sometimes as long as a month, the engraftment period.
• During this period, the donor’s T-cells that were infused along with stem cells in the graft have several important duties to perform. First, with your own immune system just about wiped out by the pre-transplant conditioning, you are wide open to every bug out there, an easy target with no defenses. This is where the donor T-cells come in. If all goes well, they will do a good job of protecting you against infections. This is called the Graft-versus-Infections effect (GVI).
• Another vital function of the donor T-cells is to seek out and kill all the remaining CLL cells in your body. Remember, this is a mini-transplant we are talking about. Most patients have at least some traces of CLL left over after the pre-treatment process, and these malignant cells would love nothing better than a chance to grow back up to full fighting levels. Giving them a chance to do that would be the kiss of death, literally. Large, well-entrenched armies of CLL cells will have a better chance of defeating the efforts of the new immune system to get rid of them. The ability of the donor T-cells to hit the ground running is important, so that they can start hunting and killing the remaining CLL cells almost as soon as they are infused into the patient. This is the critical Graft-versus-Leukemia (GVL) effect. Patients with a strong GVL response are a lot less likely to relapse. These are the folks heading for a full cure. This GVL effect is what gives the hope of a full cure and sets apart allogeneic (donor derived) transplants from autologous transplants (stem cells harvested from the patient himself).
• The third thing that donor T-cells do is not so great, in fact we wish they would not do it at all. This is the infamous Graft versus Host Disease, GVHD. Among some of the organs attacked are the full length of the GI tract, mouth, nose, and all other mucosal sites, skin, heart, lungs, kidneys, liver .. you get the picture. GVHD comes in a couple of flavors, the acute variety and the chronic variety, and each has several grades of seriousness. None of it is fun, and sometime it can be downright lethal. In fact, GVHD complications are one of the biggest causes of death after stem cell transplant. Even when the GVHD does not kill patients outright, it surely takes away from their quality of life.

So, here is the problem in a nutshell. Donor T-cells are responsible for all the trouble with GVHD. So, why can’t we nip the problem in the bud, get rid of all the T-cells in the graft before it is injected into the patient? Sounds good to you? It is actually quite easy to get rid of all the T-cells, by a process called “Campath in-the-bag”. By adding a tiny amount of Campath (also called alemtuzumab) to the plastic bag containing the precious graft, all of the T-cells in the bag are killed since T-cells display the CD52 marker that Campath targets. Stem cells are spared, since they do not have this marker. When they actually tried this approach in a clinical trial, the researchers were completely successful in eradicating all traces of GVHD. Good riddance, you say? Not quite so fast! Getting rid of the donor T-cells also reduced the necessary Graft-versus-Infections and Graft-versus-Leukemia effects. Patients did not have to deal with GVHD, but they had a lot more infections, and they also had increase in CLL relapse rates. This seems to be a case of throwing out the baby with the bathwater. Back to the drawing board.

Abstract:

Transplant Proc. 2024 Jun;36(5):1225-7.

Alemtuzumab (Campath-1H) in allogeneic stem cell transplantation: where do we go from here?

Chakrabarti S, Hale G, Waldmann H.

Department of Haematology (S.C.), Birmingham Children's Hospital, Birmingham, UK.

Alemtuzumab (Campath-1H) has been widely used for T-cell depletion following both conventional and reduced-intensity conditioning allografts. We studied the impact of alemtuzumab used in vivo and in vitro on infections, immune reconstitution, and allograft outcome. The use of alemtuzumab in vivo following reduced-intensity conditioning and unrelated donor conventional transplantation was associated with durable engraftment and significant reduction in graft-versus-host disease (GVHD) but at the cost of impaired immune reconstitution and increased infectious complications. Alemtuzumab exposure in vitro was associated with durable engraftment and reduced GVHD following conventional transplants without affecting immune recovery to the same extent. Improved results were obtained following a further reduction in the alemtuzumab dose in vitro from 20 mg to 10 mg. Subsequent pharmacokinetic studies on alemtuzumab demonstrated that the antibody persisted at a higher concentration at the time of transplant and for at least 2 months thereafter when used in vivo compared to persistence for less than 30 days when used at 20 mg in vitro. In this context; an antibody with a shorter half-life, like the original rat CD52 antibody Campath-1G, would be preferable. Otherwise, our cumulative experience with alemtuzumab suggests that better results might be achieved by tailoring the dose and mode of antibody use to match the clinical situation. Further studies are needed to optimize the dose of alemtuzumab in vivo and in vitro, determined by the type of conditioning and the graft.

PMID: 15251298
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Separating the Good GVI and GVL from the Bad GVHD

This paragraph heading says it all. If we can control GVHD without interfering with the ability of the donor T-cells in fighting infections and remaining CLL cells, we would be well on our way to making mini-donor stem cell transplants (also called mini allo transplants) a whole lot safer. A recent article gives a very nice overview of the situation, and suggests some things than can be done along these lines. The authors point to an important hint in understanding GVHD – the organs targeted by GVHD in the majority of cases are all primary or secondary barriers between your body and the hordes of killer pathogens out there.

It is easy to see how your skin and nose, lungs and airways are important in keeping out the bugs, but the mucosal lining of your mouth, stomach, the whole GI tract are equally important. We harbor an incredible variety of harmful ‘bugs’ in our GI tract, and the mucosal lining is what keeps them out, making sure they do not get into your general blood circulation. Equally important, much of the food we eat has pathogens and antigens galore. Your GI tract is a miracle of engineering, allowing the nutrients from the food you eat to pass through unrestricted, but keeping out the bad stuff.

We are all quite familiar with what happens when the mucosal barrier of the GI tract is breached. Among the things that cause breakdown of the mucosal barrier are chemotherapy drugs, antibiotics, autoimmune diseases such as ulcerative colitis, Crohn’s disease, viral infections that cause oral sores, poor dental hygiene or over aggressive brushing leading to bleeding gums, dental procedures, anything that causes a break in the mucosal barrier between your insides and the dangerous world of bugs on the outside. Diarrhea, nausea, cramps and aches, fever are all familiar signs of GI tract distress.

These authors suggest that the initiation of GVHD happens even before the graft goes in, the pre-conditioning regimen (read chemotherapy drugs and radiation) damage the mucosal linings. Cells lining the GI tract die in large numbers as a result of the toxic effects of the drugs used, and lesions are formed in the lining of the mouth and GI tract. These dying cells send out alarm signals all through the body. One of the cytokines that is tremendously upregulated as a result is the potent TNF-alpha (tumor necrosis factor alpha), which calls on all available troops to rush to defend the breach in the protective mucosal barrier. So, as soon as the new graft goes in, the donor T-cells arrive on the scene and face an immediate crisis. Sure enough, they hot-foot it to the site of damage. These donor T-cells also proliferate in huge numbers, to better take care of the crisis, and they send out even more alarm signals. In layman terms, all hell breaks lose.

GVHD is then a case of tremendous overkill. With all these alarms going off, and huge numbers of donor T-cells milling around, the crisis quickly gets out of control. In the heat of the moment and with “foreign troops” newly arrived on the scene manning the barricades, the fine distinction between friend and foe breaks down. The “Keystone Cops” kill perfectly good cells with no thought to the consequences, making things worse than they were before. The wide open lesions in the mucosal barrier means all those harmful bacteria in your gut and the antigens from half digested food have wide open access to your blood stream. Now the crisis is truly blown out of proportion.

As we have shown above, we need these darn T-cells from the donor, to protect us from infections (GVI effect), we need them to go out to kill the remaining CLL cells (GVL effect). So what else can we do to reduce the effects of the GVHD? Turns out there are several things one can do.

Action Items for Preserving Mucosal Barrier Integrity

• Discuss with your transplant team the advantages of a reduced intensity conditioning approach, the so called mini-transplant. Lower toxicity chemotherapy ahead of time means your mucosal linings are in better shape, fewer alarm bells going off to send the incoming donor T-cells on a deadly killing rampage. This is one of the major reasons why “death by therapy” has become a lot less serious in mini transplants compared to the heavy duty myeloablative transplants.
• Make sure your skin and mucosal barrier integrity is at its very best as you go in for the transplant. That means taking care of your skin, your mouth, your gut. Be sure to discuss with your transplant team any skin cancer issues.
• Dental work must get done well ahead of time. Brush your teeth often, after eating anything, but use a soft bristle brush. You do not want to have bleeding gums or micro abrasions due to scratching up the tender lining of your mouth. You may want to talk to your dentist about getting one of those new fangled “power” tooth brushes using vibrating heads. All the TV advertisements not withstanding, mouth washes with lots of alcohol are not good for you. The alcohol dries out the lining of your mouth, making it that much easier for cracks to develop. An oncological dentist I spoke with recommended a mouth wash called “Biotene” made by “Laclede”. But discuss with your dentist, he may have better suggestions for you.
• Taking care of your skin is not a sissy thing to do. You guys, keep nicks and cuts to a minimum, and take care of any unavoidable ones right away. It does not hurt to use gentle soap and skin moisturizer, I promise you will not get a sudden attack of ‘cooties’.
• Remember that old trick of eating plenty of yogurt when you get a bout of diarrhea? Turns out this is not just an old wives’ tale. Bacteria in yogurt are a friendly strain, and given a chance they will flourish and replace the much less friendly bacteria that would otherwise infest your GI tract. A couple of very recent articles in Blood (abstracts below) have the lovely titles “Let them eat Yogurt”, and I like this one even better, “Graft versus Yogurt”. You can read all about “Probiotics” and “Prebiotics” on the internet. Basically, the idea is how to introduce good bacteria into your gut (probiotics) and how to feed these good bacteria (prebiotics) so that they flourish and kick out the bad varieties. You can eat store bought yogurt and hope that has enough live cultures of the good bacteria. Or you can get a little proactive, get yourself a yogurt maker and make your own yogurt. I did, and believe me it is a very simple process, and it makes much more tasty stuff. You will need to buy the machine (around $20), as well as the starter to make the yogurt. I am sure you will be able to find models you like by a little searching, but write to me if you want to know what kind I use.
• What if you don’t like the taste of yogurt? You can check out a supplement called “Culturelle”, capsules that you can swallow. This particular brand is supposed to have an efficient form of bacteria that can survive the acid conditions of your stomach, and is therefore particularly good at colonizing your intestines.
• You are well advised to stay away from aspirin and other NSAIDS that can exacerbate ulceration of GI tract. The same thing goes for heavy alcohol consumption. Two organs that have frontline duty in handling toxins are your liver and kidneys. Be kind to them, by avoiding excessive alcohol and drinking plenty of water. Both the liver and kidneys are favorite organs for GVHD attack.
• With your best efforts, it is still very likely that there will be mucosal lesions as you go through chemotherapy, and rapid wound healing is very important. You have heard the word “angiogenesis” before, the process whereby the body constructs the blood supply to newly formed cells. This is necessary in wound healing, as well as in the formation of tumors! As you go into a transplant, it is very important to discuss with your doctor each and every supplement you are taking. For example, I hope you know EGCG and other green tea extracts are potent inhibitors of angiogenesis. If you are using this supplement, you might want to discontinue its use well in advance of the transplant. This is also true of a whole host of herbal products out there, be sure to check with your transplant team about each one you take.
• Last but not least, EPA and DHA in fish oil have been shown to reduce the production of TNF-alpha, the potent cytokine that often sets off the whole snow ball rolling in GVHD. In fact, there is a huge phase three clinical trial underway right now testing the effectiveness of fish oil capsules in inflammatory bowel disease (IBD, Ulcerative Colitis and Crohn’s disease). The origins of GVHD in terms of mucosal attack are not all that dissimilar to IBD. Dampening the fires lit by TNF-alpha may prove helpful in controlling GVHD as well.
• I have preached the value of regular and vigorous exercise as a way of improving your cardiac and pulmonary health (don’t you dare to ask me if I follow what I preach). But did you know exercise also has strong anti-inflammatory component? It causes significant reduction in the pro-inflammatory cytokine TNF-alpha. So much so that some of the transplant centers now have a treadmill in each patient’s room and the patients are encouraged to work out while they are in seclusion during their transplant.

This is a long laundry list of things you can do. None of them are unreasonable or even novel, I am sure you can understand the logic for each of the items I suggested. However, it is most likely that you will not be able to control GVHD completely, even if you follow each and every one of these suggestions to the letter. That is where your transplant team comes in. Managing the process of limiting the damaging effects of GVHD without putting too many brakes on the necessary GVI and GVL is what makes all the difference. That is why it is important to chose a transplant center that has a lot of experience. You may want to read "Transplant Centers", a PDF document that lists all the transplant centers and the numbers of transplants they have done. The list is a couple of years old, but the information is still pretty valid. It is important to consider the number of transplants done for hematological cancers as well as the total number of transplants done. The transplant game needs a team approach since many different specialists are involved. You should look for an established team that works well together. You do not want to have turf battles fought over your poor body.

Abstracts:

Article from the Journal of Clinical Investigations (Full-text article)

Editor’s Note: the link above brings up a concise and almost understandable picture of what drives GVHD in transplants.

J Clin Invest. 2024 Jun;107(12):1497-8.

Acute graft-versus-host disease: inflammation run amok?

Antin JH.

Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115

PMID: 11413153
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Blood. 2024 Jun 1;103(11):4365-7. Epub 2024 Feb 12.

Probiotic effects on experimental graft-versus-host disease: let them eat yogurt.

Gerbitz A, Schultz M, Wilke A, Linde HJ, Scholmerich J, Andreesen R, Holler E.

Department of Hematology/Oncology, Institute of Medical Microbiology and Hygiene, University of Regensburg, Germany.

Acute graft-versus-host disease (aGVHD) often limits feasibility and outcome of allogeneic bone marrow transplantation. Current pathophysiologic concepts of aGVHD involve conditioning regimens, donor-derived T cells, proinflammatory cytokines, and bacterial lipopolysaccharide (LPS) as a major trigger for aGVHD. LPS derives mostly from gram-negative bacteria and can enter circulation through the impaired mucosal barrier after the conditioning regimen. Probiotic microorganisms have been shown to alter the composition of the intestinal microflora and thereby mediate anti-inflammatory effects. We hypothesized that modifying the enteric flora using the probiotic microorganism Lactobacillus rhamnosus GG, would ameliorate aGVHD. Here we show that oral administration of Lactobacillus rhamnosus GG before and after transplantation results in improved survival and reduced aGVHD. Furthermore, subculturing of mesenteric lymph node tissue revealed a reduced translocation of enteric bacteria. Our findings suggest that alteration of the intestinal microflora plays an important role in the initiation of experimental aGVHD.

PMID: 14962899
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Editor’s Note: Lactobacillus rhamnosus GG, cited in the abstract above, is commercially available. The brand name is “Culturelle”. For more information on this probiotic: Culturelle website. We have no connections to the manufacturers of this product but to make this reference more useful to CLL patients we would appreciate feedback on the product from our readers.
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Bone Marrow Transplant. 2024 Oct;28(8):769-74.

Oral eicosapentaenoic acid for complications of bone marrow transplantation.

Takatsuka H, Takemoto Y, Iwata N, Suehiro A, Hamano T, Okamoto T, Kanamaru A, Kakishita E.

Second Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.

The 'systemic inflammatory response syndrome' (SIRS) may represent the underlying cause of complications after bone marrow transplantation (BMT). This study was conducted to determine whether blocking the etiologic factors of SIRS could improve the complications of BMT. Sixteen consecutive patients with unrelated donors were allocated alternately to two groups. Seven patients received 1.8 g/day of eicosapentaenoic acid (EPA) orally from 3 weeks before to about 180 days after transplantation, while nine patients did not. These two groups were compared with respect to complications, survival, and various cytokines and factors causing vascular endothelial damage. All seven patients receiving EPA survived and only two had grade III graft-versus-host disease (GVHD). Among the nine patients not receiving EPA, three had grade III or IV GVHD. In addition, thrombotic microangiopathy developed in four patients and cytomegalovirus disease occurred in four. Five patients died in this group. The levels of leukotriene B(4), thromboxane A(2), and prostaglandin I(2) were significantly lower in patients receiving EPA than in those not receiving it (all P < 0.01). Cytokines such as tumor necrosis factor-alpha, interferon-gamma, and interleukin-10 were also significantly decreased by EPA (P < 0.05), as were factors causing vascular endothelial damage such as thrombomodulin and plasminogen activator inhibitor-1 (P < 0.05). The survival rate was significantly higher in the group given EPA (P < 0.01). EPA significantly reduced the complications of BMT, indicating that these complications may be manifestations of the systemic inflammatory response syndrome.

PMID: 11781629
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Editor’s note: Eicosapentanoic acid, also known as EPA, is found in fish oil.