Mechanisms of Tolerance Induction by Hematopoietic Chimerism: The Immune Perspective

Abstract

SummaryHematopoietic chimerism is one of the effective approaches to induce tolerance to donor‐derived tissue and organ grafts without administration of life‐long immunosuppressive therapy. Although experimental efforts to develop such regimens have been ongoing for decades, substantial cumulative toxicity of combined hematopoietic and tissue transplants precludes wide clinical implementation. Tolerance is an active immunological process that includes both peripheral and central mechanisms of mutual education of coresident donor and host immune systems. The major stages include sequential suppression of early alloreactivity, establishment of hematopoietic chimerism and suppressor cells that sustain the state of tolerance, with significant mechanistic and temporal overlap along the tolerization process. Efforts to devise less toxic transplant strategies by reduction of preparatory conditioning focus on modulation rather than deletion of residual host immunity and early reinstitution of regulatory subsets at the central and peripheral levels. Stem Cells Translational Medicine 2017;6:700–712

Induction tolerance with donor hematopoietic stem cell infusion in kidney transplantation: a single-center experience in China with 10-year follow-up

“…It is widely believed that successful induction of chimerism is essential for the induction of immune tolerance [3,9,16,17], and the three major centers in the United States also induce different degrees of chimerism. Harvard University induces transient chimerism [18], Stanford University induces mixed chimerism, and Northwestern University induces complete chimerism [19][20][21].…”

Expansion of CD45RA−FOXP3++ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation

“…full or mixed, and durable or transient) is helpful for inducing graft tolerance following CKBMT is still unclear. 6 , 16 , 40 , 41 Moreover, underlying mechanisms of chimerism‐induced transplant tolerance are not completely understood. Our group aimed to achieve transient mixed chimerism, which requires less toxic preconditioning.…”

“…Whether donor chimerism (i.e. full or mixed, and durable or transient) is helpful for inducing graft tolerance following CKBMT is still unclear 6,16,40,41 . Moreover, underlying mechanisms of chimerism‐induced transplant tolerance are not completely understood.…”

Tolerance induction with donor hematopoietic stem cell infusion in kidney transplantation: a single-center experience in China with a 10-year follow-up

“…Our long-term follow-up results showed that none of the patients developed GVHD. Successful induction of chimerism is widely believed to be essential for the induction of immune tolerance (13,(20)(21)(22), and the three major centers in the United States also induced different degrees of chimerism. Harvard University induced transient chimerism (6), Stanford University induced mixed chimerism, and Northwestern University induced complete chimerism (3,23,24).…”