Tolerogenic Dendritic Cells as a cell therapy to prevent chronic rejection in kidney transplantation

(1)

Tolerogenic Dendritic Cells as a cell therapy to prevent chronic rejection in kidney transplantation

Elisa Molina Molina

Degree in Biomedical Sciences, Universitat Autònoma de Barcelona

The methodology consisted of bibliographic research in Pubmed and GoogleScholar databases and immunology journals including Nature Reviews Immunology, Annual Review of Immunology, Nature Immunology, Trends in Immunology.

Introduction and objectives Methodology

• To understand the immune mechanisms underlying kidney chronic rejection and expose the hallmarks of IS therapy.

• To analyse the methods for ex vivo generation of TolDCs and their therapeutic potential in transplantation.

• To propose an experimental approach to improve TolDC therapy for the treatment of chronic rejection.

The methodology consisted of a bibliographic search in Pubmed and GoogleScholar databases and immunology journals including Nature Reviews Immunology, Annual Review of Immunology, Nature Immunology, Trends in Immunology.

• The data was extensively analysed and contrasted.

• The main keywords used were, “chronic rejection”,

“kidney transplantation”, “immune tolerance”,

“dendritic cells”, “Tolerogenic dendritic cells”.

Alloreactive effector T cells migrate to renal graft

Activated donor and recipient DC and donor peptides migrate

to lymph nodes

2

3 LEGEND

Donor Recipient

MHC-I MHC-II ^Processed

peptide

Figure 1. Immunological phases of renal transplant rejection

.

Donor and recipient DCs present in the donor kidney can be activated by a pro-inflammatory context induced by renal reperfusion injury or infections. In the lymph node, donor DCs present intact donor MHC and prime CD4 and CD8 recipient T cells by direct allorecognition, and recipient DCs present processed peptides from MHC molecules in the context of self-MHC class II to restricted CD4+ T cells. Semi-direct pathway is not shown in this figure. The direct alloresponse takes place right after transplantation and is the main responsible for acute rejection, while the indirect alloresponse is considered the main pathway causing chronic rejection. Adapted from [1].

Immunological phases of renal transplant rejection State-of-the-art immunosuppression therapy for kidney transplantation

Innate response caused by reperfusion injury or infection

1 Donor alloantigens

Direct allorecognition Indirect allorecognition

Main pathway underlying

chronic rejection (months - years) Main pathway underlying

acute rejection (days-months)

CD4+

T CELL CD4+

T CELL CD8+

T CELL

DC DC DC

ACUTE REJECTION CHRONIC REJECTION

Anti- thymocyte

globulins

6 Induction phase Maintenance phase

months post-tx

IL-2 receptor antibodies

Calcineurin inhibitors mTOR inhibitors

Antiproliferative agents Corticosteroids

Tolerogenic dendritic cells (TolDCs) generation and their therapeutic potential in transplantation

Experimental proposal: promoting tolerance to HLA-I peptides to prevent CR Conclusions

PBMCs apheresis CD14

⁺

monocytes

isolation

CD14+

monocytes

Interleukin-4 ( IL-4 ) +

Granulocyte/Macrophage Colony-Stimulating Factor

( GM-CSF )

Figure 2. Current immunosuppressive treatment for kidney transplant rejection and long-term limitations.

Immature Dendritic Cells (iDCs)

Tolerogenic Dendritic Cells (TolDCs)

In vitro induction of tolerogenicity by three

possible methods

Cytokines/

growth factors Pharmacological

mediators Genetic

engineering

Dex IL-10 TGF-b

PGE

²

VitD3

DC maturation

IDO

IL-10 TFG- b

NFKb

IL-12 TNF- a

Co-stimulatory

molecules (CD80/86) and MHC-II

T-cell death-inducing Molecules (FAS-L)

Inhibitory molecules (PD-L1)

Figure 3.

Ex vivo

generation of TolDC and molecular mechanisms of tolerance.

TGF-b: Tumour Growth Factor b, VITD3: Vitamin D3, PGE2: Prostaglandin-E2, Dex: Dexamethasone, IDO: Indoleamine 2-3 dyoxigenase 1, Dex: NFKb: Nuclear Factor kb, MHC: Major Histocompatibility Complex, PD-L1: Programmed Death-Ligand 1.

Anti-inflammatory molecules Overexpression of inhibitory molecules and silencing of

activatory molecules

Immunosuppressants, organic molecules cyclic AMP inducers…

Treg

expansion

Apoptosis Inhibited

proliferation

Effects on T cells

Anergy

Antigen loading

Administration route Administration dose

Administration timing ?

? ?

Need of standardization

Study and Phase Cell product Administration

route and dosing Administration

timing Antigen loading NCT03726307

(Pittsburgh), Phase I VitD3 and IL-10

donor TolDC Intravenous

0,5-5x10⁶/kg Single injection 7 days

before Tx Unpulsed DCs NCT02252055

(Nantes) Phase I/II Low-dose GM-CSF-

recipient TolDC Intravenous

0,5-5x10⁶/kg Single injection 1 day

before Tx Unpulsed DCs

?

Kidney transplantation (KT) is nowadays a routine procedure for people with end-stage renal disease. Treatment with immunosuppressive (IS) drugs has significantly decreased acute rejection rates. However, rates of long- term kidney loss have remained rather constant over the last decades due to the persistence of chronic allograft injury. Moreover, the lack of specificity of IS drugs renders the recipient susceptible to infections and cancer in the long-term. In this sense, Tolerogenic Dendritic Cell (TolDC)-based therapy represents an innovative and promising approach to achieve kidney transplant success through the induction of immune tolerance. The objectives of this review are:

VitD

³

Table 1. Ongoing clinical trials using TolDCs for KT.

Long-term administration

Susceptibility to infections and cancer Does not avoid CR

(lack of specificity)

Donor

HLA-1 Recipient HLA-1

DQETRNMKAHSQTDRANLGT DQETTNMKAHSQRARANLGT

Sequence alignment

Analysis of mismatched regions

Peptide synthesis TolDC

pulsation Monocyte

obtention

iDCs TolDCs

IL-4 GM-CSF

Kidney recipient

Induction of tolerogenicity

HLA-I-pulsed TolDC intravenous injection

Day 1 Day -1

IS therapy

Figure 4. Experimental approach to induce specific tolerance to donor MHC-I. Recipient TolDC are pulsed with synthetized peptides corresponding to mismatched regions between donor and recipient HLA-I. Then HLA-I-pulsed TolDCs are intravenously injected 1 day before kidney transplantation. IS therapy is administered in combination with cell therapy in order to reduce the risk of early acute rejection.

• TolDC have demonstrated their therapeutic potential in transplantation, but we are still at the early beginnings of a highly promising therapy.

• Safe and efficient TolDC therapy would highly reduce the dependence on IS drugs, thus minimizing the incidence of infections and malignancies and improving long-term kidney graft survival.

• The main limitation of TolDC therapy is the lack of consensus regarding the optimal protocol for ex vivo generation. Further analysis of TolDC obtention protocols and mechanisms of tolerance will improve the potential of TolDC in transplantation.

• Siu JHY, et al. T cell Allorecognition Pathways in Solid Organ Transplantation. Front Immunol 2018;9:2548.

• Lim MA, et al. Immunosuppression for kidney transplantation: Where are we now and where are we going?

Transplant Rev (Orlando). 2017;31:10-17.

• Morelli A, Thomson A. Tolerogenic dendritic cells and the quest for transplant tolerance. Nature Reviews Immunology 2007;7:610-621.

• Ten Brinke A, et al. Ways Forward for Tolerance-Inducing Cellular Therapies- an AFACTT Perspective. Front Immunol 2019;10:181.