Dr. Alex Cuenca - Re-educating the Immune System: Old Dogmas, New Tricks in Allograft Tolerance
With Dr. Alex Cuenca
Chapter 1 of 9 · Fundamentals
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Introduction of Dr. Alex Cuenca
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Operational tolerance is defined as withdrawal of immunosuppression with normal allograft function and no histologic signs of rejection or chronic rejection.
Liver and kidney allograft survival at 5 years is greater than 80%.
Immunosuppression advances have been stagnant since about the 1990s, reflected in survival curves.
Calcineurin inhibitors cause renal vasoconstriction, AKI, CKD, diabetes, PTLD, and neurotoxicities.
An estimated 10 to 20% of liver transplant patients may be able to be withdrawn from immunosuppression, though 20% is likely high.
Ischemia-reperfusion injury releases danger-associated molecular patterns (DAMPs) that initiate inflammatory responses recruiting macrophages and neutrophils.
Antigen-presenting cells migrate to recipient lymphoid tissues and produce alloreactive effector T cells, a process occurring over the first week post-transplant.
In the thymus, T cells undergo positive selection to recognize MHC complexes, then negative selection where strong binders are deleted and intermediate binders become regulatory T cells.
Regulatory T cells in the periphery control tolerance through inducing anergy, suppression, or deletion of self-reactive T cells.
Group 2 innate lymphoid cells (ILC2s) are tissue-resident innate immune cells found in all transplanted organs and thought to provide local immunoregulatory function.
ILC2s can migrate hematogenously after stress or physiologic insult, contrary to earlier beliefs.
In heterotopic heart transplant model, ILC2s that migrate to the graft strongly upregulate MHC class II but not B7-1 or B7-2 costimulatory molecules, providing signal 1 without signal 2 and leading to T cell anergy.
In murine heart transplant model, presence of ILC2s dramatically prolongs graft survival compared to ILC2-deficient recipients; NK cell depletion does not alter this effect, confirming it is ILC2-mediated.
Cytokine-mediated expansion of ILC2s in vivo further improves allograft survival beyond baseline ILC2 presence.
Myeloid-derived suppressor cells (MDSCs) are part of the natural immune stress response, representing a 'left shift' that expands progenitor cells in bone marrow niches.
MDSCs produce immunosuppressive factors controlling innate and adaptive immune responses, but mature over time into differentiated innate immune cells, limiting their durability.
Adjuvant conditioning regimen in islet transplant model expands MDSCs and Tregs, delays rejection for approximately 3 weeks, but protection drops off thereafter.
Blocking MDSCs removes the protective effect of adjuvant conditioning; adoptive transfer of MDSCs into non-conditioned mice provides protection, confirming MDSC role.
Current immunosuppressive medications variably affect immunoregulatory cell populations (Tregs, MDSCs, ILCs), sometimes positively and sometimes negatively, potentially interfering with tolerance induction.
In Sandy Feng's multi-center trial, 12 of 20 living donor liver recipients were weaned completely from immunosuppression (original enrollment 129 patients).
DSA (donor-specific antibody) was detectable in 4 of 12 operationally tolerant patients and 7 of 8 non-tolerant patients in the Feng trial.
Five-year follow-up of the 12 operationally tolerant patients showed no progressive inflammation or fibrosis despite persistent DSA in some.
In a Japanese trial of Treg infusion in matched living donor liver transplants, 4 of 10 patients remained operationally tolerant, but the study closed early due to acute cellular rejection episodes.
Low-dose IL-2 administration to expand Tregs peripherally showed no effect in transplant patients over one month, unlike its efficacy in inflammatory bowel disease.
In kidney transplant Treg trials by Dr. Markman, 3 patients were maintained on tacrolimus monotherapy versus triple therapy after allo-anergized Treg infusion at 6 years.
In a 2005 study of 104 liver transplant patients, 45 received donor bone marrow from vertebral bodies at time of transplant; after 5 years there was no difference versus 59 controls.
In sibling-matched transplants with total lymphocyte irradiation and ATG, 17 of 22 patients were completely withdrawn from immunosuppression, suggesting memory T cell depletion improves outcomes.
Even in operationally tolerant patients from the Feng trial, long-term follow-up beyond 10 years showed a significant number developed chronic rejection, indicating operational tolerance is not complete tolerance.