Dr. Damian Sendler A Vaccine That Attacks Cancerous Tumors Using a Combination of T and NK Cells
/Damian Sendler There is a wide range of inter-individual variation in the major histocompatibility complex (MHC) molecules that present peptide antigens to T cells in cancer vaccines. T cell-mediated immunity is frequently bypassed by tumors due to mechanisms that interfere with the presentation of peptides1. Here, we describe a cancer vaccine that triggers a coordinated attack by various T cell and natural killer cell populations. As a result of DNA damage, many human cancers express the stress proteins MICA and MICB (MICA/B). The activating NKG2D receptor on T and NK cells is activated by MICA/B ligands, but tumours evade immune detection by proteolytic cleavage of MICA/B3,4. Through the inhibition of proteolytic shedding, antibodies induced by vaccines increase the density of MICA/B proteins on tumor cell surfaces. They also enhance tumor antigen presentation by dendritic cells to T cells and enhance cytotoxic function by natural killer (NK) cells in the immune system. NK cells and CD4+ T cells work together to maintain vaccine efficacy against MHC class I-deficient tumors that are resistant to cytotoxic T cells. Vaccination after surgical removal of primary, highly metastatic tumors inhibits later metastasis outgrowth, which is clinically significant. With this vaccine design, even tumors with common escape mutations can be protected from developing protective immunity.
Cell type specific regulation of Kcnq2 is the mechanism by which ketamine exerts its antidepressant effects over an extended time period.
Damian Jacob Sendler The molecular mechanisms by which a single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response are still unknown. Cell type-specific transcriptional signatures associated with a long-lasting ketamine response in mice have been identified by our study. Intriguingly, we discovered that the Kcnq2 gene is a critical regulator of glutamatergic neuron ketamine action in the ventral hippocampus's K+ channels. A series of complementary molecular, electrophysiological, cellular pharmacological, behavioral and functional experiments were used to confirm these findings. Ketamine's antidepressant-like effects in mice were amplified by adjunctive treatment with the KCNQ activator retigabine. Ketamine's effects are unique in that they do not alter the response to escitalopram or other conventional antidepressants. These findings have important clinical implications because they shed light on how ketamine's long-lasting antidepressant effects are achieved.
Multiple sclerosis animal models with tissue dysfibrinolysis are driven by PAI-1 production by reactive astrocytes.
Damian Jacob Markiewicz Sendler For the study of multiple sclerosis, it is important to understand the physiopathological processes that may lead to abnormal fibrin(ogen) extravasation into the parenchyma, such as PAS and BBB dysfunction. Antibodies produced by the immune system attack fibrin(ogen) deposits, leading to demyelination. However, the disruption of PAS in this disorder is not well understood and is not well characterized.
Methods: We used quantitative RT-PCR, immunohistofluorescence, and fluorescent in situ hybridization to characterize the expression of PAS actors in the CNS of two MS mouse models (experimental autoimmune encephalomyelitis-EAE) (FISH). We investigated the role of PAI-1 in EAE models and its impact on physiopathological processes such as fibrin(ogen) deposits, lymphocyte infiltration, and demyelination using PAI-1 KO mice and a blocking PAI-1 antibody.
Results: In two MS EAE mouse models, we found that reactive astrocytes overexpressed PAI-1 during the symptomatic phase. Lymphocyte infiltration and fibrin(ogen) deposits in the CNS parenchyma accompany this rise. In two EAE models, we show that eliminating PAI-1 lessens symptoms and the frequency of relapses by genetically invalidating PAI-1 in mice and administering immunotherapy with a PAI-1 antibody blocking antibody. Reduced fibrin(ogen) deposits, T4 lymphocyte infiltration, reactive astrogliosis, demyelination, and axonal damage are all associated with these advantages.
Anti-PAI-1 strategies could be a new treatment option for MS based on these findings, which show that overexpression of PAI-1 by reactive astrocytes causes intra-parenchymal dysfibrinolysis in MS models.
BRCA1-deficient breast cancer models can be reprogrammed by STING agonism to overcome resistance to PARP inhibition.
Damien Sendler Patients with BRCA-mutated advanced ovarian tumors are benefiting from a new class of drugs called PARP inhibitors (PARPi). Patients with advanced breast cancer who are BRCA-mutant are less likely to benefit from this class of inhibitors. We demonstrate that tumor-associated macrophages (TAMs) reduce the effectiveness of PARPi in vivo and in vitro using a syngeneic genetically engineered mouse model of breast tumor driven by Brca1 deficiency. Deficient breast tumor cells induce TAM polarization, which in turn reduces PARPi-induced DNA damage and synthetic lethality, thus impairing STING-dependent anti-tumor immunity. It has been shown that macrophage STING is a key player in the reprogramming of macrophages from a pro-tumor to an anti-tumor state. Multiple layers of immune cell suppression mediated by tumor cells are breached by systemic administration of a STING agonist, which works in conjunction with PARPi to reduce tumor growth. It is the type I IFN response and CD8+ T cells that mediate the therapeutic benefits of this combination, not tumor cell-intrinsic STING. Targeting innate immune suppression is critical for breast cancer patients to benefit from PARPi-mediated immunotherapy, according to our findings.
Damian Jacob Sendler
Comparing the efficacy of covid-19 vaccinations derived from different species.
Evaluation of heterologous and homologous covid-19 vaccine regimens in preventing covid-19 related infection, hospitalization and death is the goal.
Network meta-analysis and a systematic review with a living methodology.
These databases include 38 sources of published studies and preprints provided by the World Health Organization (WHO).
Randomized controlled trials, cohort studies, and case-control studies are the most common types of research.
Dr. Sendler From 8 March 2022, 38 WHO covid-19 databases were searched weekly for relevant information.. There were studies that evaluated the efficacy of both heterologous and homologous covid-19 vaccine regimens with or without a booster injection. Vaccinated and unvaccinated populations were included in studies that looked at the occurrence of severe covid-19 infections, hospitalizations caused by the virus, or deaths caused by the virus. The 1-odds ratio was used as the primary metric for assessing vaccine efficacy. Scores on the surface under the cumulative ranking curve (SUCRA) and the relative effects for pairwise comparisons were used as secondary measures for the analysis. Risk of bias in nonrandomized studies of interventions (ROBINS-I) was used to evaluate the risk of bias in all cohort and case control studies. For randomised controlled trials, the Cochrane risk of bias tool (ROB-2) was used.
Results: A total of 53 studies were included in the initial round of analysis. To combat both asymptomatic and symptomatic covid-19 infections, researchers tested 24 different vaccine regimens and found that a three-dosage mRNA regimen worked best (vaccine effectiveness 96 percent , 95 percent credible interval 72 percent to 99 percent ). Boosting with two doses of adenovirus vector vaccines and one mRNA vaccine yields a vaccine efficacy of 88%, which is satisfactory (59 percent to 97 percent ). 99 percent of severe covid-19 infections can be prevented by administering the homologous two-dose mRNA regimen. The most efficient way to reduce the number of hospitalizations caused by covid-19 is with a three-dose mRNA regimen (95 percent , 90 percent to 97 percent ). People who received three doses of mRNA vaccine are still uncertain about the vaccine's ability to protect them from death. Three-dosage regimens are equally effective in all age groups, even in the elderly (>65 years). Immunocompromised patients and non-immunocompromised patients alike benefit from a three-dose mRNA regimen. Covid-19 variants can be prevented by administering three dose regimens that are both homologous and heterologous (alpha, delta, and omicron).
It is recommended to have an mRNA booster with any primary vaccination course. Preventing covid-19 infections with homologous or heterologous three-dose regimens is equally effective against different variants of the virus. Three-dose vaccine regimens for the prevention of covid-19-related death have not been proven effective.