Inflammation and the balance of Treg and Th17 cells in transplant rejection and tolerance.
OBJECTIVE
Inflammation of the allograft, occurring as a consequence of hypoxia and ischemia/reperfusion injury, adversely influences short-term and long-term transplant outcomes. Thus far, imbalance of tissue-protective Treg and tissue-destructive Th17 cells has been confirmed in a number of tissue-inflammatory states, including autoimmune disease. Hence, benefits of tilting Treg-Th17 equilibrium toward dominance of Tregs may promote transplant tolerance.


RESULTS
Adverse graft inflammation creates extreme resistance to the induction of donor-specific tolerance. Proinflammatory cytokines, when abundantly expressed within the graft and draining lymph nodes, prevent commitment of donor-activated T cells into graft-protective, T-regulatory phenotype, while fostering generation of donor-reactive Th1, Th2 or Th17 effector subsets. In addition, the inflammatory milieu may destabilize the program of both natural and induced Tregs, converting them into inflammatory, effector-like phenotypes. Therefore permanent, Treg-dependent acceptance of an allograft may not be achieved without limiting adverse tissue inflammation.


CONCLUSIONS
Balance of graft-protective regulatory and graft-destructive effector T cells largely depends on the balance of proinflammatory and anti-inflammatory cytokines in the milieu, in which donor-directed T-cell response occurs. In the absence of proinflammatory cytokines, the constitutive expression of TGF-beta may guide recipient T cells into a tissue-protective, pro-tolerant mode. Therefore, targeting adverse tissue inflammation may represent a powerful means to tilt antidonor immunity towards tolerance.
Hanidziar
Dusan
D
Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, USA.
Koulmanda
Maria
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology* / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects; D014184:Transplantation, Homologous
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D020381:Interleukin-17