GENERAL MEDICAL NEWS
The staff of The Reproductive Times here offers brief referenced notifications on interesting general medical and scientific news with broad relevance to reproductive medicine and biology. Some of these news items may become subjects of more detailed reporting in The Reproductive Times on later occasions. The purpose of these short notifications is to give readers the opportunity to get immediately more detailed information by looking up the reference of the notification.
The relevance of adjuvants for vaccines
Adjuvants are supposed to boost the adaptive immune response. The process by which a vaccine enhances immunity against infectious agents or other diseases is complex and involves many different cell types. A recent preprint – CAUTION PREPRINT – tried to inform about these processes. The reporting Chinese investigators demonstrated in a mouse model a potential mechanism by which adjuvants impact the exogenous peptide repertoire presented by MHC II molecules (1).
A commentary then noted that by altering which peptide antigens are presented to CD4+ T cells, adjuvants affect the specificity of the immune response (2).
REFERENCES
1. Li et al., eLife , July 16, 2024. Reviewed reprint. https://elifesciences.org/reviewed-preprint/99173
2. Rapaka RR. eLife August 13, 2024. https://elifesciences.org/articles/101259?utm_source=content_alert&...um=email&utm_content=fulltext&utm_campaign=14-August-24-elife-alert
Progress in autoimmune diseases
EULAR 2024 (European Alliance of Associations for Rheumatology) which this year took place in Vienna, Austria, promised interesting and very welcome new developments regarding the treatment of several major autoimmune diseases often seen in women during reproductive years. Systemic lupus erythematosus (SLE) is one very good example. Apparently at least 17 phase-2 and 14 phase-3 trials are expected to start in the near future, including B-cell-targeting agents, plasma cell-targeting agents, and drugs with novel mechanisms of action (1).
A very “hot” issue for many autoimmune diseases at the conference were treatments with CAR-T cell therapy, and not only in SLE. A recent paper in Cell, for example, reported on three patients who received CR-T therapy for severe myositis and systemic sclerosis (2). Healthy-donor-derived CD19-targeting CART cells were engineered using CRISPR-Cas9 to address immune rejection and were then infused into the three patients. Infused cells persisted for over three months. Complete B cell depletion was achieved within two weeks. At 6-months follow-up, patients went into deep remission, without complications (like cytokine storm). The patients also demonstrated reversal of inflammation and fibrosis. These preliminary results suggested that this treatment—introduced to human practice of course in oncology—appears relatively safe and produces strong immune modulatory effects.
Maybe most importantly, the study suggests that the cells for CAR-T treatment no longer must be autologous but that they could be ordered “off the shelf.” What this also starts to suggest is that such treatment may also be used during pregnancy.
Going to another promising treatment, CD4+FOXP3+ regulatory T cells (Tregs), are known to play a central function in preventing autoimmunity. When they dysfunction, autoimmunity can occur but the molecular processes underlying this are unknown. An international consortium of researchers now offers some clarity: in multiple sclerosis (MS) patients, they looked at essential transcription programs regulating autoimmunity in these patients. What they found was an aberrant PRDM1-S/SGK1 axis which led to destabilization of forkhead box P3 (FOXP3) and Treg dysfunction. And most interestingly, they also found this abnormal axis in other autoimmune diseases.
Emergence of PRDM1-S and epigenetic priming of AP-1/RF may, thus, be a key driver of dysfunctional Tregs leading to autoimmune diseases (3)
Considering the close interconnectivity of autoimmunity and pregnancy (a state not only of considerable self-tolerance but also of allogeneic tolerance), one wonders what these findings may mean for pregnancy abnormalities driven by tolerance defects?
References
1. Freeman S. Medscape Medical News. August 1, 2024. https://www.medscape.com/viewarticle/multiple-investigational-approaches-show-promise-treatment-2024a1000e5y
2. Wang et al., Cell 2024;187:4890-4904
3. Sumida et al., Sci Transl med 2024;16(762):eadp1720
At least some humans can fight (most) infections even in absence of tumor necrosis factor (TNF)
Here is one example of how science constantly offers unexpected results. We are talking about tumor necrosis factor (TNF), a key signaling molecule in our immune system (until recently called TNF-alpha). In response to an antigen, it is primarily produced by activated macrophages and induces inflammation. It may boost a person’s immune response but may also cause cell necrosis and cell death (1). It is a so-called cytokine and—through a variety of mechanisms involving the regulation of inflammation and cell death—protects many species from infections.
And here is the paradox: Roughly 50 years ago, TNF was discovered in mice infected with mycobacterium, the microorganism causing tuberculosis (2). Considering TNF’s central role in fighting infections and its evolutionary conservation, the widely held opinion has been that mutations of the gene encoding TNF that eliminate its function, would prevent affected individuals from reaching adulthood. This conclusion was reached based on several animal models and the observation that anti-TNF treatments which have become very popular in treating chronic inflammatory diseases are often complicated by life-threatening infections, especially from Mycobacterium tuberculosis (3).
Now, however, a very large international consortium of investigators reports on two patients (cousins) who lack all TNF activity, are surprisingly healthy, which means that they are able to prevent most infections, but are susceptible to tuberculosis (4). Gene-expression analyses and other studies of the two individuals revealed nothing unusual regarding their immune cells or gene-expression profiles in absence of tuberculosis. They, indeed, responded completely normal to other cytokines.
Those fascinating findings—as always in science—raise many more questions, the principal one, of course, being: why are these two cousins are immunologically competent against all other infectious agents (the study suggested that there may be also mildly diminished protection against Listeria monocytogenes)? Discovering what kind of redundancies may be effective in protecting these two cousins from other infections in complete absence of a TNF response would, of course, allow the development of new anti-infectious treatments, a very urgent need at a time of ever-increasing drug resistance to available treatments.
References
1. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/tumor-necrosis-factor
2. Carswell et al., Proc Natl Acad sci USA 1975;72:3666-3670
3. Pyle CJ, Tobin DM. Nature 2024;633:293-294
4. Arias et al., Nature 2024;633:417-425
Some good news regarding recurrent or refractory chronic graft-versus-host disease (GvHD) and why it may matter for reproductive medicine
Chronic graft-versus-host disease (cGvHD) is a very frequent complication of allogeneic hematopoietic stem cell transplantation, the only curative treatment for bone marrow failure. The pathophysiology is based on infused allogeneic stem cells viewing the recipient’s cells as a threat and starting to attack them. The clinical presentation of cGvHD mimics an autoimmune-like inflammatory disease affects 50% of long-term bone marrow transplant patients and is fatal in 20-40% of cases (1). First line treatment is still high dose systemic corticosteroids, but several biologicals are also increasingly used, as is the mammalian target of rapamycin (mTOR) and other drugs. However, no standard second-line treatment has yet been established (2).
Both acute and chronic GvHD result from an initial insult that triggers an exaggerated inflammatory cascade of events, with first symptoms usually involving the skin and oral mucosa in the form of a maculopapular rash (3). Because such rashes also occur in pregnancy—especially in the third trimester—the specter that pregnancy may be complicated by GvHD-like conditions has been raised.
More specifically, acute GvHD can occur in neonates as consequence of a maternal-fetal and in mothers due to fetal-maternal transplacental transfusions during pregnancy and can develop into cGvHD if going unrecognized. This, of course, should not surprise because the fetal-placental unit is during normal pregnancy a seemingly well-tolerated semi-allograft (and full allograft in cases of egg donation or gestational-carrier pregnancies) within the maternal environment, until it no longer is well-tolerated, which usually means that the end of pregnancy has been reached.
That a recent paper in The New England Journal of Medicine reported that a drug called Axatilimab is quite successful in treating recurrent or refractory cGvHD (4) is, therefore, of interest for reproductive medicine. It is well known that colony-stimulating factor 1 receptor (CSF1R) – dependent monocytes and macrophages are essential mediators of cGvHD. Axatilimab is a CSF1R-blocking antibody.
References
1. Berger et al., Bone Marrow Transplant 2008;42(suppl 2):S101-S105
2. Shiratori et al., Int J Hemat 2024. https://doi.org/10.1007/s12185-024-03850-9
3. Ramachandran et al., Dermatol Clin 2019;37(4):569-582
4. Wolff et al., N Engl J Med 2024;391:1002-1014