Tolerogenic Dendritic Cells on Transplantation: Immunotherapy Based on Second Signal Blockage

Abstract

Dendritic cells (DCs), the most important professional antigen-presenting cells (APC), play crucial role in both immunity and tolerance. It is well known that DCs are able to mount immune responses against foreign antigens and simultaneously tolerate self-antigens. Since DCs can be modulated depending on the surrounding microenvironment, they can act as a bridge between innate and adaptive immunity. However, the mechanisms that support this dual role are not entirely clear. Recent studies have shown that DCs can be manipulated ex vivo in order to trigger their tolerogenic profile, what can be a tool to be used in clinical trials aiming the treatment of various diseases and the prevention of transplant rejection. In this sense, the blockage of costimulatory molecules on DC, in the attempt of inhibiting the second signal in the immunological synapse, can be considered as one of the main strategies under development. This review brings an update on current therapies using tolerogenic dendritic cells modulated with costimulatory blockers with the aim of reducing transplant rejection. However, although there are current clinical trials using tolerogenic DC to treat allograft rejection, the actual challenge is to modulate these cells in order to maintain a permanent tolerogenic profile.

Figure 1

Schematic representation of the DC and T cell interaction: the main costimulatory molecules. Activation of T cell involves both interactions between the T cell costimulatory receptors, CD28 with their cognate ligands, CD80, and CD86 (B7 family) as well as the CD40L/CD40 pathway. Other costimulatory molecules, such as OX40/OX40-L and TIM-1 and PD-1/PD-L1, were not represented here. DC: dendritic cell; MHC II: major histocompatibility complex II; TCR: T cell receptor; CD40L: CD40 ligand.

Figure 2

Mechanism of action of CTLA4-Ig on DC. CTLA4-Ig soluble molecule binds to B7 (CD80/CD86) molecules on DC. CTLA4 presents a higher affinity to B7 molecule and competes with CD28 for this ligation. This interaction induces downregulation of B7 gene transcription and upregulation of IDO as well as secretion of sHLA-G. sHLA-G can stimulate Th2 and inhibit Th1 profile. DC: dendritic cell; CTLA4-Ig: extracellular domain of human CTLA4 with a portion of the Fc region of IgG; IDO: indoleamine 2,3-dioxygenase; sHLA-G: soluble HLA-G; Th: T helper; IL: interleukin; IFN: interferon; TNF: tumor necrosis factor.

Figure 3

Hypothetical mechanism of action of CTLA4-KDEL fusion protein. Transport of proteins between the ER and Golgi apparatus is mediated by two membrane coat complexes, COPI and COPII. COPII mediates ER-to-Golgi transport and COPI mediates retrograde transport. KDEL receptor undergoes retrograde transport only after it binds its ligand [147]. On CTLA4-KDEL transfected cells, the KDEL peptide retains/retrieves proteins to the ER. CTLA4 fused to KDEL is confined to the ER where it binds CD80/86, preventing the passage of these molecules to the cell surface. CD80/CD86 molecules seem to be removed by proteasome-mediated degradation. GC: complex of Golgi; N: nucleus; ER: endoplasmatic reticulum; CTLA4-KDEL: gene construct encoding a modified CTLA4 molecule; COP: cytosolic protein coat complex.

Figure 4

Anti-CD40L interaction and effects on T cells. Costimulatory molecule CD40L is primarily expressed on activated CD4⁺ T lymphocytes. Anti-CD40L binds to the CD40L present on T cell and blocks its interaction with CD40 receptor present on APC. Therapy with anti-CD40L (CD154) or anti-CD40 MAb, alone or combined with other molecules, downregulates T cell proliferation, Th1 cytokine production, and antibody secretion. CD40L: CD40 ligand; APC: antigen-presenting cell.