Transplantation: Innate Alloimmunity and Transplant Tolerance

"Innate immunity is an evolutionarily highly conserved, rapid first line of host defence against invading pathogens in different multicellular organisms, including insects and plants. In mammals, this host defense system precedes adaptive immunity where dendritic cells represent the bridge by translating informative events of innate immunity into antigen-specific events of adaptive immunity," Professor Dr. Walter Land (Munich) emphasizes in his new textbook "Innate Immunity and Allograft Rejection".

"Modern research data clearly indicate that innate immune defense is not only directed against pathogen-induced tissue injury but against any tissue injury, including reactive oxygen species-mediated injury to allografts occurring under donor brain death condition and allograft reperfusion in the recipient.

This implies that, in the situation of organ transplantation, we are dealing with two innate immune systems: that of the donor and that of the recipient. Accordingly, we can differentiate between donor-derived dendritic cells already residing in the allograft during implantation and recipient-derived dendritic cells entering the allograft during reperfusion in the recipient. Both types of dendritic cells, following transplantation, travel from the donor organ to the recipient´s secondary lymphoid tissue where, as immunostimulatory, ”immunogenic” dendritic cells, they stimulate/activate naïve recipient T cells under presentation of allogeneic peptide antigens.

In fact, maturation of immature donor- and recipient-derived dendritic cells into immunostimulatory “immunogenic” cells must be regarded as the key event of innate alloimmunity; a molecular process which is induced via the primary oxidative allograft injury, and to which innate lymphocytes contribute via direct cell-to-cell-contact. The basic reaction/interaction of this process is the recognition of so called damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) on dendritic cells. It is this injury-induced maturation process which leads to those immunostimulatory, “immunogenic” capacities of dendritic cells, and which is characteristically associated with up-regulation of 3 signals: signal 1 = up-regula­tion of allopeptide-complexing MHC-molecule expression; signal 2 = up-regulation of costimulatory molecule expression; signal 3 = secretion of Th1-cell-polarizing cytokines such as members of the interleukin-12 family, associated with the establishment of an inflammatory milieu and mainly influenced by the activation of intracellular inflammasomes.

Recent insights into molecular mechanisms of innate immunity indicate that dendritic cells do not only provoke an adaptive immune response but, in terms of tolerogenic dendritic cells, are also able to actively induce an immunological tolerance. Thus, immunologists, using various sophisticated experimental designs, succeeded in generating tolerogenic dendritic cells which enabled the researchers to induce true immunological tolerance.

In order to successfully generate tolerogenic dendritic cells, it seems to be of utmost importance to avoid the establishment of an inflammatory milieu, that is to inhibit the up-regulation of signal 3 or even signal 2 and 3. In regard to successful induction of transplant tolerance, this would mean to prevent initial oxidative injury to an allograft. Transplant clinicians should be aware of this aspect of innate alloimmunity when designing and elaborating on future research projects."