Table 10.
Immunomodulating agents applied to allotransplantation and potential candidates for xenotransplantation clinical trials.
| Immunomodulating agents | Mechanism of action | Specific use | pig-to-NHP Xenotransplantationa | |
|---|---|---|---|---|
| FDA approved for transplantation | ||||
| Induction | Anti-thymocyte globulin | Polyclonal Ab from horses or rabbits immunized with human thymocytes, T-cell depleting | ACR | Heart, islets |
| Basiliximab | Inhibition of IL-2 receptor (CD25), T-cell non-depleting | PKP, islets | ||
| Belatacept, abatacept | Prevent interaction between CD80 and CD86 receptors on the antigen presenting cell and CD28 on the T cell | Islets | ||
| Maintenance | Cyclosporine A | Inhibition of the enzyme calcineurin by binding of cytoplasmic cyclophilin A/D | ||
| Tacrolimus | Inhibition of the enzyme calcineurin by binding of FKBP-12 | PKP | ||
| Azathioprine | Inhibition of the cell cycle by antagonizing purine metabolism | |||
| Mycophenolic acids | Inhibition of the lymphocyte cycle by blocking inosine monophosphate dehydrogenase | Kidney, heart, islets | ||
| Sirolimus, everolimus | Inhibition of the enzyme mTOR by binding of FKBP-12 | Heart, islets | ||
| Belatacept, abatacept | Prevent interaction between CD80 and CD86 receptors on the antigen presenting cell and CD28 on the T cell | Islets | ||
| FDA non-approved, commercially available | ||||
| Corticosteroids | Binding of the glucocorticoid receptor | ACR, AMR | PKP, LKP, DSAEK, kidney, heart, islets | |
| Alemtuzumab | Binding of CD52, T-cell depleting | |||
| Intravenous immunoglobulin | Modulating antigen presenting cell activity and compliment activation | Desensitization, AMR | PKP | |
| Rituximab | Monoclonal Ab against CD20 | Desensitization, AMR | PKP, heart | |
| Bortezomib | Reversible inhibitor of the 26 S proteasome Suppression of Ab production from mature plasma cells |
Desensitization, AMR | ||
| Eculizumab | Blockade of the C5b-9 membrane attack complex | Desensitization, AMR | ||
| C1 esterase inhibitor | Inhibition of compliment system | Heart | ||
| Fingolimod | Sphingosine-1-phosphate receptor agonist | Islets | ||
| Efalizumab | Blockade of interaction between leukocyte function associated antigen 1 and intracellular adhesion molecule | Islets | ||
| Etanercept, adalimumab | Anti-tumor necrosis factor-alpha inhibitor | Heart, islets | ||
| IL-1 receptor antagonist | IL-1 inhibitor | Heart | ||
| IL-6 receptor antagonist | IL-6 inhibitor | Heart | ||
| Under investigation | ||||
| Anti-CD154 Ab | Blockade of CD40−CD154 costimulatory signal | PKP, kidney, heart, islets | ||
| Anti-CD40 Ab | Blockade of CD40−CD154 costimulatory signal | PKP, LKP, heart, islets | ||
| CD4R1 | Rhesus recombinant CDR-grafted anti-CD4 Ab | Kidney | ||
| M-T807R1 | Mouse/rhesus CDR-grafted form of the depleting anti-CD8a Ab | Kidney | ||
| Cobra venom factor | Inhibition of compliment system | Islets | ||
| Regulatory T cells | Induction and maintenance of peripheral tolerance | Islets | ||
| Regulatory B cells | Development of peripheral tolerance | |||
| Tolerogenic/regulatory dendritic cells | Development of peripheral tolerance | |||
| Mixed chimerism | Development of central and peripheral tolerance | |||
Abbreviations: Ab: antibody, ACR: acute cellular rejection, AMR: antibody-mediated rejection, CD: cluster of differentiation, CDR: complementarity determining region, DSAEK: Descemet stripping automated endothelial keratoplasty, FDA: Food and Drug Administration, FKBP: FK506-binding protein, IL: interleukin, LKP: lamellar keratoplasty, mTOR: mammalian target of rapamycin, NHP: non-human primate, PKP: penetrating keratoplasty.
a
Immunosuppressive drugs used in successful combinations that enabled long-term survival of porcine xenotransplants (more than 6 months) in non-human primate recipients.