MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Terapie - Imunostimulace u DM1

ATG or alemtuzumab with TNFalpha inhibitors

  • Duration of insulin independence provided by transplanted islets was increased when
    • Fc-receptor non-binding, anti-CD3 and ATG, or alemtuzumab with TNFalpha inhibitors are used
  • ATG and antibodies against TNFalpha antibodies
    • Have demonstrated potential to expand Treg cells
    • Consistency with inducing tolerogenicity to transplanted beta cells via restoring Treg to effector T-cell homeostasis
  • diabetes.diabetesjournals.org/content/60/1/1

Abatacept and belatacept

  • Effector T cell recognises an antigen presented on either major histocompatibility complex (MHC) I or II,
  • The B7 family binds to either costimulatory CD28 or co-inhibitory CTLA-4
  • Binding of the B7 ligands to CD28 is necessary for activation of effector T-cell function
  • CTLA-4 competes with CD28 for binding to B7 ligands to inhibit this activation
  • CTLA-4 binds to B7 ligands with a higher affinity
  • Recombinant CTLA-4 fused to Ig - abatacept and belatacept
    • Attempt to exploit co-inhibition
  • CTLA-4 is fused to Ig to increase its half-life

Clinical trials prove that

Abatacept

  • An arthritis drug
  • Can delay type 1 diabetes progression a year after treatment has been discontinued
  • Studies again funded as part of JRDF’s Restoration program
  • www.diabetes.co.uk/Diabetes-Cure.html

Adalimumab and etanercept

Alemtuzumab


Anti-CD25

Antibodies are used to suppress Th17 signalling

    • Brodalumab binds to the IL-17 receptor
      • Approved for certain autoimmune diseases
  • Th17 cells are also involved in T1DM
    • Clinical trials are required to reveal whether antibodies that suppress Th17 signalling have therapeutic effects in T1DM

Teplizumab

    • An Fc-receptor non-binding
    • Anti-CD3 monoclonal antibody
    • Obstructs the transmembrane assembly of CD3 subunits within the T-cell receptor (TCR)
    • Prevents signalling downstream of the TCR and therefore mimics effector T-cell exhaustion

Monoclonal antibodies JES6-1 and F5111.2

Antithymocyte globulin (ATG)

  • ATG, a polyclonal antibody that suppresses lymphocytes and other immune cell types
  • Through diverse mechanistic pathways to prevent acute rejection
  • Induce the expansion of Treg cells ex vivo
  • A single course of low-dose ATG
    • Delays the decline of C-peptide levels at 1 year after infusion
  • diabetes.diabetesjournals.org/content/60/1/1

Bacillus-Calmette-Guerin (BCG) vaccine

Faustman Lab at Massachusetts General Hospital clinical trial program

Možná, že to, že se přestalo očkovat proti TBC, může souviset s nárůstem DM1.

In 9 humans with type 1 diabetes

  • None are “cured”
  • Most experienced significant reductions in insulin needs.

Phase IIb clinical trial underway

  • Will read out in as early as 2022
  • Because of the size of our Phase II trial and BCG’s known safety profile and its generic drug status
    • We are hoping to pursue approval coming out of Phase II trial
  • Faustman adds that the BCG vaccine has demonstrated a clear and clinically significant response
    • In the primary endpoint for type 1 diabetes trials
      • A stable and long-term return of blood sugars to the near normal range for over 5 years without hypoglycemia.
  • diabetesstrong.com/cure-for-type-1-diabetes/

CRISPR/Cas 9

Cyclophosphamide and anti-thymocyte globulin

  • Profound immunoablation
  • Followed by rescue with autologous bone marrow transplantation to prevent the theoretical risk of aplastic anemia that could, in theory, develop after the cytoreductive-induction treatment
  • However, this risk should be virtually absent since the induction is not fully cytoablative.
  • Additional strategies continue to be explored including cellular approaches such as the use of immature autologous dendritic cells
  • diabetes.diabetesjournals.org/content/60/1/1

Diabetes vaccine Selecta Bioscience

  • Synthetic Vaccine Particle (SVP) as an immunotherapy for type 1 diabetes.
  • Reprogram the immune system
  • To prevent inflammatory responses to insulin cells
  • Currently trialling SVP on mice courtesy of funding from JRDF
    • A leading global organisation funding type 1 diabetes research
  • www.diabetes.co.uk/Diabetes-Cure.html

Edmonton protocol

  • Anti-lymphocyte globulin and small molecules (cyclosporine, azathioprine, and glucocorticoids)
  • For islet transplantation
  • Glucocorticoids
    • Adversely stimulate gluconeogenesis in the liver and antagonise the insulin-mediated uptake of glucose
    • Induction of peripheral insulin resistance is counterproductive
  • Glucocorticoid-free regimen consisting of:
    • Sirolimus, tacrolimus, and daclizumab
  • Sirolimus - rapamycin
    • Macrolide that binds to FKB12
    • Blocks the activation of the cell-cycle specific kinase TOR
    • Indirectly inhibits the proliferation of T cells and B cells
    • Biphasically induces insulin resistance
  • Tacrolimus
    • Structural similarity to sirolimus
    • Inhibits calcineurin with a much stronger potency compared to cyclosporine
    • Significantly lower dose of tacrolimus is therefore required
    • Considered the risk-averse alternative to cyclosporine
    • Risks associated with calcineurin inhibitors, including
      • Decline in renal function and dialysis, are not sufficiently eliminated
    • Causes beta-cell dysfunction
  • Cotreatment with a GLP-1 agonist
    • Suggests that these counterproductive effects are reversible and can be prevented
  • Daclizumab
    • Monoclonal antibody that blocks the CD25 subunit of the IL-2 receptor
    • Decreases IL-2 signalling at this high-affinity receptor
    • Increased availability of IL-2, it inadvertently increases IL-2 signalling in cells expressing intermediate-affinity receptors
    • Ameliorates autoimmunity with clinically meaningful effects, immune-mediated risks are concerns
    • Reported serious inflammatory disorders and death
      • Use is restricted and monitored

Exosomes

  • Released via autocrine, paracrine, or endocrine signalling
  • Minute (30–150 nm) spherical sacs of phospholipid bilayer, exosomes enclose a cargo of proteins, mRNA, and microRNA (miRNA)
  • Exosomes are isolated from the interstitial fluids or specific cell types for diagnostic or therapeutic purposes
  • Exosomes isolated from specific cell types are a potentially versatile therapeutic tool.
  • MSC-derived exosomes
    • Enclose IL-2, IL-4, IL-10, TGFbeta1, IDO, proteins, and miRNA
      • Suggested to regulate the expression of IL-6, IL-17AF, IL-12p70, and IL-22
  • MSC-derived exosomes are preferred over MSC
    • Because of a lack of tumourigenicity
    • Lower risk of becoming trapped in the lung microvasculature
    • Ability to evade immune recognition
    • Modifiability of the cargo via transfection with therapeutic nucleic acids
  • Protective effects of MSC-derived exosomes
    • Due to suppressed differentiation of naive T cells into the Th17 cell lineage
    • First clinical trial to investigate the potential of MSC-derived exosomes to ameliorate T1DM
    • Has not yet published results
  • CD8+ T cells
    • Perform cytotoxic activity in a contact-dependent manner
  • CD4+ T cells
    • Mostly perform via paracrine signalling
  • Treg cells
    • Rich source of exosomes that contain
      • Immunosuppressive proteins, mRNA, and miRNA
  • Developed via transfection
    • Dominant negative form of IKK2, Fox3+CD25- Treg cells
    • Secrete exosomes with a unique set of miRNA and isoform nitric oxide synthase mRNA
  • When engulfed by target T cells
    • The miRNA and isoform nitric oxide synthase from these exosomes
      • Inhibit the transcription of cell-cycle proteins
      • Induce apoptosis
  • T cells are targeted by direct exposure to exosomes in ex vivo assays
    • A strategy that facilitates the in vivo engulfment of exosomes by autoreactive T cells is needed
  • Exosomes are formed by inward buddings of endosomal vesicles derived from the plasma membrane
  • Isolating exosomes from TCR Treg cells is a potential strategy
    • Engineered TCR are embedded within the membrane of the exosomes
  • To increase the output of the exosomes with embedded TCR per cell
    • Exosomes are steered toward the autoreactive T cells
    • Accumulate in its vicinity
  • Overexpressing key receptors for receptor-mediated endocytosis
    • Can be exploited to induce uptake of exosomes
  • Exosomes with embedded TCR that recognise the peptide–HLA complexes most frequently encountered in T1DM
    • Can be manufactured for off-the-shelf therapeutic use
  • www.emjreviews.com/diabetes/article/advanced-approaches-in-immunotherapy-for-the-treatment-of-type-1-diabetes-mellitus/

Fc-receptor non-binding anti-CD3



GAD vaccine


IL-2

IMCY-0098 - ImotopeTM

Phase 2 clinical trial – IMPACT

  • Specifically targets the autoimmune response destroying insulin-producing cells without harming the rest of the immune system.
  • A short-term disease modifying treatment with potential long-term effect in Type 1 diabetes
  • Good safety through a targeted approach in a Phase 1 study

Phase 2 clinical trial

  • IMCY-0098 450 mcg, IMCY-0098 1350 mcg, placebo
  • To evaluate the ability of IMCY-0098 to stop diabetic progression in newly diagnosed patients
  • As well as to determine the best and safe dose and regimen for continued development
  • Will initially recruit adult patients newly diagnosed T1D
  • Multi-centre, clinical trial with sites located across Europe in Belgium, the United Kingdom, Sweden, Slovenia and Italy.
  • Will enrol 24 participants, aged 18-45
    • Randomly assigned to one of three treatment arms
    • Follow patients for up to 48 weeks
  • Will explore the immune signature and safety of the treatment comparing two different doses with placebo
    • To determine the best dose and regimen for IMCY-0098
  • Second step should recruit 60 adults between 18 and 45 years
    • Planning to also include, with supportive safety data, adolescents aged 12-17 to evaluate the treatment effect
  • Results are expected after step one is completed in Q4 2021.
  • An Independent Data Monitoring Committee consisting of renowned international experts
    • Will supervise the study to ensure the safety of the patients
  • Study comprises a total of 10 (first step) or 11 (second step) visits over the course of approximately 52 weeks

Infusing cells with immunosuppressive therapeutic behaviours

CD4+CD25+Fox3+ Treg cells

Mesenchymal stem cells (MSC)


Isolation of autoreactive T cells and overexpression of Foxp3

  • Is another approach
  • Issues with instability
  • Foxp3 is critical for maintaining the functionality of Treg cells
    • Targeting epigenetic regulators and post-transcriptional modifiers are opportunities to enhance stability
  • Treg cells has ability to lose Foxp3 expression
    • And acquire an effector T-cell phenotype
  • Engineering suicide signalling pathways that can be easily triggered by small molecules, in the event that Treg cells become unstable, is a strategy to prevent from paradoxically exacerbating autoimmunity.

Lactococcus lactis bacteria genetically modified

  • To express proteins, peptides, antibodies or human cytokines
  • Our guts are familiar to this bacterium, as it’s used to produce cheese and buttermilk.
  • In the case of type 1 diabetes, the bacteria are engineered to produce the
    • Insulin precursor human proinsulin
    • Interleukin 10
  • Together they signal the gut-associated lymphoid tissue, where immune cells are stored, to restore the tolerance of insulin-producing cells with the goal of slowing down or stopping their destruction.

Phase I/II clinical trial in the US and Europe in people with type 1 diabetes as young as 12 years old


Multipotent MSC

  • Therapeutic cells
  • Via paracrine secretion, MSC release:
    • TGFbeta, prostaglandin E2,
    • Hepatocyte growth factor,
    • Indoleamine-pyrrole 2,3-dioxygenase (IDO)
    • nitric oxide,
    • IL-2, IL-4, IL-10,
    • Galectin-1
  • With the exception of hepatocyte growth factor, the released molecules mediate immunosuppression
  • In the presence of the TGFbeta and IL-2
    • Naive T cells are known to differentiate
    • Expand into CD25+Fox3+ Treg cells
  • IDO
    • Catalysing the rate-limiting step of tryptophan metabolism,
    • Renders effector T cells and dendritic cells ineffective
  • nitric oxide is an immunomodulator
    • Activity is concentration-dependent yet not uniform
  • A dose- and frequency-dependent association between the infusion of MSC
    • And the preservation of insulin secretion suggest causality
  • When infused, MSC reduced exogenous insulin requirement
    • By one-half for 2 years
    • Curbed HbA1c levels for 3 years
  • While MSC are the most clinically studied cell-based therapy
    • Inconsistent results have clouded therapeutic efficacy
    • Have indefinitely delayed FDA approval

Otelixizumab


Rituximab


Rituximab


Biologics to restore regulatory T cell to effector T-cell homeostasis.

Increase IL-2 signalling

  • JES58-1 and F5111.2 preferentially bind to IL-2 receptors on Treg cells and induce its expansion.
  • Humanised versions are in development

Increase TNFalpha signalling

  • Adalimumab and etanercept
    • Trimerise TNFalpha receptors on Treg cells and induce its expansion.

Increase CTLA-4 signalling

  • Recombinant CTLA-4 fused to Ig - abatacept and belatacept
    • Exploit co-inhibition and divert away from CD28 co-activation.

Decrease IL-17 signalling

  • Brodalumab
    • Binds to IL-17 receptors to suppress downstream signalling that activate autoreactive CD8+ T cells.

Decrease TCR signalling



The adoptive cell transfer of autologous Treg cells

  • May be the safer counterpart to aHSCT for the majority of T1DM patients who do not have underlying IPEX syndrome
  • Extirpating the recipient’s immune system is unnecessary
  • Morbidity from GVHD is not a concern
  • Several good manufacturing practice-compliant protocols for the isolation of autologous Treg cells from peripheral blood have been established
  • Isolation of a low quantity of Treg cells is sufficient
    • Small molecules and biologics can be used to induce the ex vivo expansion of Treg cells with high purity
  • Adoptive cell transfer of autologous Treg cells induces tolerogenicity
  • Clinical trials are underway to determine whether it can efficaciously ameliorate autoimmunity
  • Treg cells are more potent when genetically engineered to express
    • Chimeric antigen receptors (CAR)
    • TCR that bind preferentially to peptide–HLA complexes
  • CAR bind to peptide–HLA complexes at higher affinities
    • Binding to higher quantities of antigen is a requisite for sufficient activation of signalling downstream of CAR

Infusion of regulatory T-lymphocytes (T-regs)


Teplizumab


Neovacs kinoid immunotherapy - anti TNF-alpha vakcína

  • Based in France
  • Block this excess cytokine production to stop autoimmune diseases
  • Vaccine that stimulates the immune system to neutralize interferon alpha
  • Interferon alpha in excess induces the appearance of immune cells that attack and destroy insulin-producing cells
  • Can stop type 1 diabetes by neutralizing the excess of interferon alpha
    • Induces the immune system to produce antibodies against interferon alpha
  • Neovacs has already tested the same vaccine in people with lupus
    • Results have shown that the vaccine can keep the patients immunized for 5 years.
    • This means that a person with type 1 diabetes would only need to receive an initial treatment of 6 months and then a booster every 4 to 5 years.
  • www.labiotech.eu/in-depth/immunotherapy-type-1-diabetes/

Cyclosporin and methotrexate

  • Induces remission in type 1 diabetes mellitus
  • [Douglas O. Sobel, Annette Henzke, Val Abbassi . Acta Diabetologica , Volume 47, Issue 3, pp 243-250]
  • High-dose cyclosporin (cyclo) has been demonstrated to induce remission of type 1 diabetes mellitus (T1D)
    • Limited by its toxicity
  • Methotrexate (mtx) and cyclo synergistically inhibit autoimmune processes

Pilot study

  • Insulin dose requirements and glycemic control were compared in
    • 10 new onset T1D control children
    • 7 children who were administered
      • Cyclo at 7.5 mg/kg/day for 6 weeks
      • Then 4 mg/kg/day in addition to mtx 5 mg/kg/wk for 1 year
  • After 6 weeks, cyclo doses were adjusted to maintain blood cyclo levels 110–220 ng/ml.
  • All children were treated with two daily injections of insulin.
  • There were only very minor adverse effects and no drug induced biochemical test abnormalities.
  • Mean HbA1c levels were similar in the experimental and control groups at baseline
    • And at 3, 6, and 9 months
    • But was lower in the cyclo + mtx group at 12 months
  • Daily insulin requirements of the groups were similar at baseline
    • But lower in the cyclo + mtx group at 3, 6, 9, and 12 months.
  • no control subjects became non-insulin requiring
    • Four of seven cyclo + mtx-treated subjects were entirely off insulin therapy for 2.5, 4.5, 8, and 12 months
  • Low-dose cyclo and mtx treatment of subjects with new onset T1D
    • Can safely induce remission of disease and decrease the amount of required insulin.
  • www.diabetesni.org/research/type-1-diabetes-is-there-a-cure/

Natural Cures for Type 1 Diabetes: A Review of Phytochemicals, Biological Actions, and Clinical Potential

  • Placený obsah

Ostrůvky beta buběk transplatnace

  • 17 people who have received islets from a donated pancreas
    • Seven have stopped using insulin completely
    • Many of the remaining people now require less insulin and have better diabetes control.
  • Problem with transplantation of islets
    • Need to be given islets from more than one organ donor
    • People who receive the transplant need to take powerful immunosuppressive drugs
  • Secret to transplant success lies in the islets
    • Trying out ways to modify the islet genetically
      • So it will survive the transplantation process
  • Islets don’t like being extracted from the pancreas
  • When you transplant into a recipient, it’s estimated that up to 70% will die within the first 24 to 36 hours
  • They are very fragile
  • Genetically engineering an islet graft with anti-inflammatory compounds
    • Is sufficient to allow permanent survival for the majority of the grafts
    • Achieved in the face of a very strong immune attack in the recipient and in the absence of any immunosuppression
    • Modified islet grafts engender regulator T cells that stop the attack of the warrior T cells
      • Resulting in long-term islet graft tolerance

Vaccine BCMA-Fc

O úroveň výše

Poslední aktualizace: 31. 7. 2022 0:54:03