This is an extremely long post because it’s something I feel strongly about, not just for my investment. HLH is something I’m on the alert for in my family. Also, a very expensive “miracle” drug I decided against importing years ago (our GP prescribed something else) has turned out to be a lot less effective than its marketing made out. (A friend who works in the pharmaceutical industry recently told me it inhibits the “wrong” cytokines but I’m questioning that entire strategy.
I don’t have a science background and welcome any corrections. My intention is to learn about immunology.
Remestemcel-L and Sepsis, the Best Possible Match?
At the last AGM, SI showed one science slide and said it was the only science slide - the cytokine storm one familiar to many of us. He made the same statement and showed the same slide in the Share Cafe presentation.
Much of the literature describes acute GvHD as a heterogeneous cytokine storm. The same is said of sepsis. Physicians familiar with GvHD will be familiar with sepsis because it’s not uncommon after HSCT:
In the study by Zaidman et al. (2023), out of the ten children who died, sepsis is listed as a reason for death in five.
The incidence of sepsis is increasing and my next post will focus on my reasons as to why.The mortality rate for severe sepsis is 30% to 40%. It’s said to be the most expensive condition to treat because it usually involves ICU.
Sepsis is notoriously difficult to treat because it involves a complex interaction between the adaptive and innate immune system, which is not fully understood, as is the pathophysiology of sepsis itself. There are no approved treatments.
Cau et al. (2023) present some facts about sepsis:
Sepsis is a dynamic disorder of dysregulated inflammatory and immune responses.
Heterogeneity is present in patients with sepsis.
There are currently no effective therapeutic options available for sepsis in the clinic.
Individualized immunotherapy based on the individual immunological characteristics of sepsis patients is a reasonable and promising therapeutic option.
The traditional school of thought was that sepsis involves a period of hyperinflammation followed by a state of immunosuppression, which makes the timing of treatment particularly challenging.
There’s increasing evidence, however, that these states can be simultaneous. Hotchkiss et al. (2013) say:
“Traditionally, the host immune response to sepsis was considered to be characterized by an initial hyperinflammatory phase that evolved over several days into a more protracted immunosuppressive phase7,8,9(theory 1)However, recent studies have shown that both pro-inflammatory and anti-inflammatory responses occur early and simultaneously in sepsis18,19,20(Fig. 1a)”
Nevada et al. (2019) say inflammation in sepsis is “a necessary evil.” They review the “catalog of failures” in drug trials in sepsis. Flawed animal models did not represent the heterogeneity of sepsis in humans.
Therapies targeting pro-inflammatory cytokines such as tumor necrosis factor (TNF-α) led to increased mortality in that it increased infections.
(This is known to be the case with Infliximab in GvHD. Note Infliximab as “best available choice” for 17 patients in Reach 2)
Qiu et al.(2013) did a meta-analysis and found a modest but significant effect in anti TNF in sepsis. The authors are right IMO to look at subgroups in trials for this heterogeneous condition; however, they say that for a trial to be properly powered, at least 10 000 patients would have to be recruited.
Nevada et al. say:
“Sepsis is a biphasic disease, the initial phase is characterized by overwhelming inflammation followed by immuno-suppression. A homeostatic balance between these two competing events is to be achieved for the patient’s recovery.”
Cau et al. (2023) also review the trials targeting inflammation in sepsis and say all anti-inflammatory therapy strategies failed:
“Many patients with sepsis have a relatively brief phase of hyperinflammation, so the success of drugs targeting inflammation may be effective only for a very short period of time. Patients with sepsis may also become immunocompromised, so a “one-size-fits-all” treatment strategy for sepsis-induced immune imbalance is bound to fail. In general, precise regulation of the excessive inflammatory response and immunosuppressive state of the body in sepsis patients is the key to treating sepsis”
Sepsis or HLH?
HLH can be misdiagnosed as sepsis. Marle et al. (2023) say HLH has an overall mortality rate of 40%.
Based on my reading, there’s consensus that prompt diagnosis is important because treatment is different. You can find case studies where the patient died quickly because initial treatment was for HLH, which later turned out to be sepsis and vice versa.
Transplant physicians will be familiar with HLH. It’s separated into primary (familial) and secondary. Primary HLH usually affects children and one common treatment for it is HSCT.
Secondary HLH can be caused by viruses, infection, malignancy or they can be iatrogenic, occurring after CAR T therapy or allo- HSCT:
Garg et al. (2020) reported on cases of 4 patients suffering HLH following BMT. Three patients died and there was graft failure in the only survivor.
Sandler et al. (2019) review studies in sHLH (secondary HLH) following allogeneic HSCT:
“The investigators propose that the higher incidence following allogenic HSCT may indicate that sHLH is a form of GvHD, in that activation of host macrophages, in response to donor stem cells,give features of GvHD, similar those of sHLH.”(My emphasis)
Dr. Jessica Rose is IMO one of, and the front for, a group who are the world’s most brilliant immunologists. She didn’t just pop up from nowhere. She came to global attention in the FDA’s blatant ADCOMs publicly available on YT.
A year ago, Dr. Rose was contacted by a mother whose daughter aged 12 died from HLH. Dr. Rose investigated, finding a signal that cases were increasing.
A hematologist commented that HLH used to be extremely rare but she’d seen a “huge uptick” in cases; the first nine years of her career she saw one case but in the previous two years she had five. She says HLH is likely underreported because it requires a bone marrow biopsy for diagnosis.
Dr. Rose wanted her readers (who include physicians and scientists) to watch the short video by Dr. Eric Strong MD (first link below).
Dr. Strong says two tests are important but not often done: Check for lower NK cell activity andelevated IL2 receptor(aka CD25). Cattaneo et al. (2016), who report appalling survival in HLH, say these tests were not available for most patients.
THAT Drug Where Ryoncil Should Be AGAIN!
I acknowledge my strong bias against Rux in the condition of SR acute GvHD for reasons I’ve already given.
Also, I saw Rux approval as a major red flag because I figured that once approved, many patients (including children under 12) would have been given it. I worried that Ryoncil could be moved from steroid refractory to steroidandRux refractory.
GIven cells respond to the inflammatory milieu of an individual, what does being refractory to Rux mean in terms of that milieu? Broad jAK inhibition increases infections. Would there be more of them? What about a partial response? Don’t MSCs signal through the JAK Pathway?
( 67% survival in 51 adults and children gives a strong signal of the cells’ potency, considering the salvage position. Some of those patients would have been in a desperate way before being referred to our EAP.)
Cai et al. (2015) say the JAK/STAT signaling pathway is key in sepsis. Bloch et al. (2023) say cytokines involved in HLH syndrome activate the JAK/STAT pathway in immune cells, particularly gamma- interferon through JAK1.
JAK1 inhibitor Itacitinib has been studied in non-severe secondary HLH in adults and a trial is ongoing.
Zhang et al. (2023) say, “Since many of the elevated cytokines in HLH signal through the JAK-STAT pathway, many preclinical and clinical studies demonstrated the efficacy of using JAK1/2 inhibitor, ruxolitinib, for the treatment of HLH… Its potential as a cytokine inhibitor andits affinity for CD25were initially assessed through molecular docking, aiming to aid targeted HLH therapy.” (My emphasis)
Ruxolitinib is being trialed in secondary HLH in combination with Dexamethasone. (I’ve read that Dex is the preferred steroid for HLH because of its ability to cross the blood brain barrier.)
You”ll find pilot studies online of Ruxolitinib in HLH where follow-up was relatively short. This is a concern because, as Hill et al. (2021) say, durable results in GVHD are “less robust” and that broad JAK inhibition is linked to an increased risk of opportunistic infections.
People with Crohn's Disease are more susceptible to HLH because many are on immune suppression. Li et al.(2015) say the two main causes of HLH in IBD patients are infection with cytomegalovirus and Epstein-Barr virus. I’d think this would be the case in rheumatic disorders such as juvenile idiopathic arthritis.
A Double-Edged Sword
When I first started learning about immunology, I read up on pro-inflammatory cytokines and anti-inflammatory cytokines. IL-6, for example, I saw as one of the “bad guys” and IL-10 one of the “good guys.”
I later learned IL-6 is important for gut homeostasis. Alhendi et al. (2023) discuss the dual role of IL-6 in Crohn’s Disease:
“IL-6 exhibits diverse functions that range from maintaining the intestinal epithelium integrity and mucosal barrier function to the modulation of immune response against environmental microbes.”
(IL-6 blocker Actemra is known to increase the risk of heart attacks. My theory is that if gut integrity is damaged, the translocation of bacteria and endotoxins can damage the heart (gut/heart axis). Vioxx was taken off the market due to a high incidence of heart attacks. It was also known to cause GI effects.)
Of sepsis, Chaudhry et al. (2023) write:
“A high IL-10-to-TNF-α ratio was associated with death. Furthermore, persistent overproduction of IL-10 is the main risk factor for sepsis severity and fatal outcome (69), suggesting that patients with sepsis are in profound immunosuppression.”
I wondered if the same could be true of interferon gamma, which plays critical roles not only in orchestrating both innate and adaptive immune responses against viruses, bacteria, and tumors, but also in promoting pathologic inflammatory processes.
@JB1975 in this post#:73218648you said:
“Interferon gamma is a pro-inflammatory cytokine that would normally contribute to not mitigate any cytokine storm.”
Obviously “normally” is the key word here but in your following paragraph, if I understand your context correctly, you say if it’s increasing then something is going wrong and that you’ve shown that “MSBs own data shows that inf gamma increased on at least one occasion.”
Firstly, I ask what’s normal in a heterogenous cytokine storm? Also, I wonder about “any” cytokine storm because there’s disagreement in the literature about that too:
Merli et al. (2021) say.
“Notably, there is no widely accepted definition of “cytokine storm”19; moreover, there is uncertainty about the distinction between cytokine storm and physiologic inflammatory response.”
Whether sepsis and Covid are characterized by hyperinflammation or immune suppression, it looks like the cytokines play different roles depending on the milieu.
Todorović-Raković et al. (2021) say of Covid-associated disease:
“The understanding of IFNγ actions - whether immunomodulation and immunotolerance are independent or overlapping phenomena - is more complicated by the fact that during disease
progression, there is a time-dependent subtle balance of immunity cascades when “less is more” and/or vice versa.”
IFN-γ in Sepsis and HLH
Chaudhry et al. (2010) discuss the role of cytokines as a “double edged sword in sepsis.”
Authors say:
“IFN-γ expression was enhanced persistently in patients who died of sepsis (13), however, treatment of IFN-γ neutralization did not improve survival consistently (45). Furthermore, survival after sepsis was associated with the improvement of the pro-inflammatory, but not the anti-inflammatory response.”
Of HLH, Merli et al. (2021) say:
“What is clear is that HLH is essentially a spectrum of related disorders that share clinical and immunologic features, but have different (albeit related) etiologies. For this reason, the North American Consortium for Histiocytosis (NACHO) recommends to categorize HLH subtypes based on specific etiology subgroups” (rather than “ambiguously” categorizing as primary and secondary).
Authors say: “Several groups have observed that IFN-γ is essential for the development of HLH”; however, they acknowledge HLH isn’t fully understood and the studies cited are in animal models. Animal models poorly represent the pathophysiology of sepsis in humans. Perhaps that’s also the case with HLH.
Emapalumab (a human anti–interferon-γ antibody) was approved for pediatric primary HLH on the basis of a single trial.
Out of 34 children, there were 10 deaths and a high rate of severe infections.This is a concern if, like sepsis, sufferers of HLH enter a state of immune suppression.
A trial in Emapalumab for secondary HLH (in rheumatic disorders where HLH is termed macrophage activation syndrome) is under way. As in the case of the trial in children with pHLH, this one in adults and children is open label andSINGLE ARM,which is what you’d expect in a condition where there’s no SoC and the high mortality rate is well known!
Cattaneo et al. (2016) report on a single center case series of 35 adult patients suffering HLH of different etiologies. They found four year survival and HLH-free survival was 17.8% and 23.8% respectively. If you look at the chart, seven patients died in around a week. The authors concluded “there was a statistically significant trend for viral infection to be a predictor of poor prognosis.”
IFN-γ in GvHD and IBD
Haring et al., 2021 (Zeiser, investigator of the Reach trials, is a co-author) discuss the heterogeneous effects of interferons in intestinal GvHD and IBD (Crohn’s Disease and ulcerative colitis) which share multiple key features, notably the involvement of interferon cytokines.
Authors say the role of interferons remains controversial. They cite studies which indicate IFN-γ has detrimental effects on the intestinal epithelium but others which indicate it can be protective.
In IBD, Haring et al. correctly say that so far the only anti cytokine therapy that’s been successful is anti TNF. (Infliximab is by far the best but many patients are now refractory and surgery rates remain high.)
Anti-IFN therapy (such as the use of Fontolizumab in CD and Eldelumab in UC) has failed.
I think interferons' role in intestinal inflammation isn’t very well understood because, despite being a fairly recent paper, many of the studies Haring et al. cite are in animals. Further, the authors say a Type III interferon family has recently been discovered.
IFN-γ in Severe Covid
Covid 19 could lead to sepsis in severe cases. Opoka Winiasker et al.(2020) even askif HLH could be at the core of severe Covid cases! (That could explain the vascular effects observed early on.)
There's a difference of opinion on whether severe Covid was a cytokine storm at all. Remy et al. (2020) say that Covid is characterized by severe immune suppression, not a cytokine storm.
Todorović-Raković et al. (2021) say:
“Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury.”
Of proinflammatory cytokines in Covid patients, authors say:
“Circulating cytokines in COVID-19 patients, at least early in their clinical course, did not show widespread elevation. Most COVID-19 patients had either no elevation or only mild increases in the major proinflammatory cytokines including TNF-α, IL-1α, IL-1β, IFN-ɣ, etc.”
Specifically of IFNγ, Todorović-Raković et al. conclude:
“Discrepancies and contradictions of numerous studies are a reflection of the complex role of IFNγ during various pathophysiological conditions.”
Hu et al. (2020) say:
“The basal circulating IFN-γ levels were comparable with c-reactive protein in the discrimination of the occurrence of lung fibrosis among COVID-19 patients at discharge, unlike circulating IL-6 levels. In conclusion, these data indicate that decreased circulating IFN-γ is a risk factor of lung fibrosis in COVID-19.”
(I said before that I'd ask at the next AGM for an update on results in under 65 survivors on the ARDS trial. If they’re doing better than SOC + placebo, that would speak to lack of fibrosis but the healing process is very complex.)
IFN-γ in Cancer
When I researched this, I was surprised to learn that sepsis and cancer share features and that this is well known. There’s disagreement as to the role of interferon-gamma in cancer too:
Jorgovanovic et al. (2020) say:
“Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. Authors say it has been “reported that tumors treated with low-dose IFN-γ acquired metastatic properties while those infused with high dose led to tumor regression.” IFN-γ is considered potentially useful for adjuvant immunotherapy for different types of cancer”
“A key player in driving cellular immunity, IFN-γ is capable of orchestrating numerous protective functions to heighten immune responses in infections and cancers.”
The Microbiome
Then the topic I’ve been banging on about for years: the microbiome (which includes the virome) and is a smoking hot research area.
Emeritus Professor Robert Clancy is an expert in mucosal immunology and practising physician. In the interview linked below, he discusses the role of the microbiome in immunity. He says one important research finding from Covid was that people who became severely unwell had gut dysbiosis.
He says microbiome researchers and mucosal immunology researchers used to be separate but now they’re coming together because the thinking is it should be viewed as a single system. (Prof Clancy even dislikes the term gut/lung axis because it’s unequivocally one mucosal system.)
Prof Clancy discusses the success of fecal transplant in IBD. He sees Crohn’s patients who are on various mabs, which he says are “just a sophisticated kind of steroid” because they suppress the immune system (They’re often given in combination with the thiopurines, which also suppress the immune system.)
Professor Paul Moayeddi is highly respected in mainstream IBD. I mentioned here some years ago that he’d reviewed trials in FMT and said the current thinking is that IBD is not an autoimmune condition but the immune system reacting to an antigen that was (“presumably”) microbial.The current treatment paradigm therefore is entirely wrong!!
What has this to do with us? IMO the data are very compelling but I don’t see FMT as a magic bullet. (The pediatric first pilot RCT in UC excluded a lot of patients and had difficulty recruiting.) IMO FMT and MSCs are likely to be complementary. Medicinal signaling cells must surely play a role in communication between the host immune system and the microbiota (The short chain fatty acids Professor Clancy refers to as critically important induce regulatory T cells.)
Professor Caplan (RIP) specifically mentioned MSCs’ positive action on bacteria and endotoxins in his lecture available on YT. Alcayanda-Miranda et al. (2017) found MSCs have direct and indirect antimicrobial effects. One way is through the secretion of antimicrobial peptides and proteins (AMPs). Authors say IFNy can upregulate the expression of AMPs. Since I first mentioned this paper some years ago, it’s become very highly cited.
IMO the most important finding is the work by Nagashima et al. (2017) who discovered sub-epithelial mesenchymal cells which not only induced gut microbiota diversity but also regulated the production of IgA, which preserves gut intestinal immune homeostasis.
(I also wonder if breach of gut IgA in the presence of endotoxins could trigger a cytokine storm such as MIS or HLH and if this mechanism specifically could be causing the increase in cases? I’m particularly interested in any thoughts on this.)
Nagashima et al.’s discovery is important because more diverse gut flora are well known to be a major factor in long-term survival in GVHD.
The Case for MSCs in Sepsis and/or HLH
Since I started researching MSCs at the start of 2016, I noticed that over time, the terminology changed from “immunosuppressive” to “immunomodulatory.”
Khan et al (2019) say, "The secretome of MSC contains both pro-inflammatory (e.g., TNF-alpha, IFN-gamma, and IL-1B) and anti-inflammatory cytokines (e.g., TGF-beta 1, IL-13, and IL-18 binding protein), with the net effect likely to be the result of a balance between the two".
Much of the literature on sepsis and HLH stresses the importance of “a delicate balance” or “a fine balance.” I just don’t see what could achieve that other than MSCs?
If I recall right, SI, being an immunologist, mentioned once in a webcast the benefits of inflammation but knows if it overshoots, organ damage can occur.
Unlike Ruxolitinib, Remestemcel-L has been trialed and got good results in a sepsis-like condition in under 65s and finding a synergy with Dexamethasone.
(I’ve been following and cheering on a highly orchestrated attack on a cabal which controls big food and pharma and has deliberately fostered a sick care industry. Medical professionals in the US fighting for ethics slammed the in-hospital Covid treatment protocol, saying it was killing patients. Critical care specialist Professor Paul Marik called the use of Dexamethasone “A homeopathic dose of the wrong steroid.”
Interestingly, the only expert from the counter attack I’ve come across who thinks Dex was the right steroid for Covid is Angus Dalgleish! The more low key IMO, the higher up the chain of command. Having listened to him, I suspect he’s one of the forces behind immunotherapy in cancer. You can look up the discoveries on T cells attributed to him and the boards he’s sat on.)
IMO the most crucial thing of allis that coagulation disorders occur in sepsis and HLH. Levi et al. (2016) say “Severe sepsis is almost invariably associated with systemic activation of coagulation. Hemorrhagic brain disease can result from disseminated intravascular coagulation (DIC). Ling et al. (2021) say DIC has been observed in nearly 50% of HLH cases.
Guillamat-Prats (2022) discusses how MSCs regulate coagulation in a wide range of pathways, and it’s highly relevant IMO that:
MSB’s MPCs reduced GI bleeding in LVAD recipients
P3 Dream showed reduced risk of strokes
Ryoncil specifically targets grades C and D GI which must surely include cases of hemorrhage
MSB’s product healed a case of grade 4 intestinal hemorrhaging
Remestemcel-L has been used in MIS-C which is known to be a cytokine storm similar to HLH. (If you look in the supplementary index, you’ll see Yousaf et al. (2022) excluded a case of MIS-C for the alternate diagnosis of HLH.)
Last but not least, there’s the (pending?) patent for TNFR1 andIL2Ra!
In conclusion, I think the days of mabs and nibs are numbered, along with drugs that block or inhibit. It’s clear that we don’t know enough about the human immune system to interfere with a multivariable control system without causing downstream effects.
A major theme of the past four years has been the importance of acknowledging and confronting hubris (which is the key message in the interview with Prof Clancy - they’re not just talking about IBD). I can’t say what the future will bring but I’m hopeful because I think this revolution is in good hands.
Our cells IMO are obviously ideal for conditions of highly dysregulated immune response such as GvHD because, to borrow the words of a young man cured by them, they “know what to do.”
All IMO
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(20min delay)