Transplant approachs for T1D

objectives:

Transplant approaches for the management of T1D

Current Status of beta cell replacment therapy

challenges facing beta cell replacment therapy

new advances to improve transplant function

Currently exogenous insulin is used in the clinic, where there is an ongoing bacttle of hyperglycemia and hypoglycemia that a patient endures.

  • there are two main routes for insulin therapies: exogenous (artifical pancreas) and beta cell replacement therapy

Beta Cell replacemnt therapy:

  1. Whole organ pancreas transplant - aims to restore natural insulin production, but requires lifetime immunosuprresion 9this means that the patient must take medication for the rest of there life so that there immune system doesn’t self attack)

    • may still be insulin dependent

    • hypoglycemia is the main indication

    • complications are hypoglycemia at night

  1. Islets cell transplant - you infuse insulin producing islet cells from a donar pancreas into the liver where they produce insulin.

  • an islet is the body’s glucostat

  • requires immunosuppresives

Long-term function is achievable - insulin dependence rates do decline overtime, but there is graph burnout overtime but it is unknown why. approximately half of the islets will die when infused due to inflammation and self attack

  • patients survival, and sever hypoglycemia are really well accounted for in trials

    • 60% optimal glycemica control, 70% reduction in insulin doses, 30-60% insulin independence

  • Results are highly dependent on the center’s experience!!

Islet cell transplant is considered a fourth line therapy where there is very strict criteria

  • severe hypoglycemic event in the past year

  • episodes of hypoglycemia and maladaptive behavior

  • HbA1C greater thann 7.5

  • time in hypoglycemia greater than 5%

  • glycemic lability

Diabetes related complications:

retinopthay = stabililization of retinopathy

neuropathy = understudied but some improvements

nephropathy = confounded by use of immunosupressants

CVD = plaque stabilization and improvement in ECG

quality of life = improved quality of life observed in hypoglycemic related distress

Current and future challenges:

  • majority of islets destroyed with hours to days due to post-tx

  • multiple donars per recipients

  • life long whole body immunosuppression

  • finding an ideal transplant site

    • immune privileged sites = eye chamber, spleen, omentum

    • non-immune privileged sites = subcutaneous space, hepatic protal vein, bone marrow

      • the eye chamber is advantageous because its easy access, high oxygen, immune priveledged, peripheral tolerance

      • subcutaneous devices stimulate angiogenesis, but didn’t see a metabolic benefit

  • encapsulation

    • stem cells trials

    • exogenous oxygen supply

    • xenotransplantation

  • Main limiation of adding foreign stuff to the body 

    • Hypoxia, inflammation, fibrosis, improper materials, cost, reproducibility, device failure

Microencapsulation

  • coated in alginate, this stops the immune system from attacking itself

  • a challenge is delivery high oxygen to the encapsulated cells

Optimizing biomaterial:

  • zwitterionic polymers - lowbiofouling meaning that they don’t adhere to other cells and hence are carrying a positive and negative charge and make a hydrophilic coating

    • helps prevent fibrosis

  • resistant protein adsorption and cell adhesion

    • this aims to stop immune cells from attaching and initiating immune responses

  • combine with ultra pure alginates

    • allow glucose and insulin exchange but block immune cells

  • drug eluting coating

    • help reduce inflammation

Open encapsulation - designed to improve oxygenation and nutrient supply through a semi-permeable device design with an immune barrier so only nutrients like insulin and glucose can permeate.

  • reduce foreign body response

  • retrievable - it can be replaced if it becomes fibrotic

  • facilitate mass transfer - this means exchange of oxygen, nutrients, glucose, and insulin

  • localized allogeneic protection - prevent rejection without need for immunosupressive drugs

  • Ultimate goal is prevascularized and local immunosuppression - 

    • Prime the localized cells and increase T reg cells to reduce risk of transplant procedure

design considerations::: you want to mimic the natural environemtn, where you implant, ideally no immunosupression, matabolic demands