Chimerism, graft-vs-host disease, rejection, and their association with reciprocal donor-host immune reactions after cell, organ, and composite tissue transplantation

Abstract

We have postulated that a small number of donor-derived leukocytes and the recipient immune system mutually interact and reciprocally attenuate both host-vs-graft (HVG) and graft-vs-host (GVH) reactions.1 Multiple cell and organ transplant models confirm the coexistence of donor cell traffiking and graft acceptance.2 However, the outcome of GVH and HVG reactions after drug discontinuation remains unpredictable. In this study, we hypothesize that both the graft's antigenicity and migratory cell load playa determinant role in the development of chimerism, graft-vs-host disease (GVHD), and rejection during the final drug-free stage. MATERIALS AND METHODSBN recipients underwent different cell, organ, or composite tissue allografts from LEW donors. Immunosuppression involved short (28 days) or prolonged (100 days) treatment with tacrolimus (1 mg/kg/d IM for 14 days, then weekly). Cell inoculi (spleen, bone marrow) and organ allografts (liver, heart, small bowel) were studied and compared to composite tissue allografts (CTA; rat hind limb) which conversely offer both a strong antigenic barrier as well as a continuous source of viable migratory donor leukocytes (ie, vascularized bone marrow). 3 RESULTS AND DISCUSSIONFollowing short-term immunosuppression, tolerogenic allografts (bone marrow, liver) reached long-term survival and tissue-detectable microchimerism (Table 1). Only heart allografts, with high antigenicity and low migratory cell load, underwent moderate to severe chronic rejection and disappearance of mixed tissue microchimerism by flow cytometric techniques. Those allografts with a heavy migratory cell load such as the bone marrow, spleen, and small bowel presented significant expansion of tissue and peripheral chimerism and concomitantly, the greatest incidence of GVHD. Bone marrow inoculi displayed low GVHD susceptibility. CTAs, which are highly antigenic and contain the greatest viable migratory cell load, underwent delayed rejection after short-term immunosuppressive coverage. However, when exposed to prolonged immunosuppression, the chimeric expansion was allowed to stabilize throughout tacrolimus coverage. After its discontinuation, transient, nonlethal GVH reaction ensued in 9 of 13 animals. Their recovery was then consistently followed by slow reduction of cytometrically detectable chimeric leukocytes from peripheral blood, repopulation of the donor bone marrow with recipient elements, and allograft chronic rejection. Of notice, allografted

Reciprocal Donor-recipient Strain Combinations Present Different Vascularized Composite Allotransplantation Outcomes in Rodent Models

“…20 In a hindlimb LEW-to-BN VCA model, administration of FK506 for 28 and 100 days elicited transient GvHD, followed by rejection and chronic rejection, respectively. 21 The in vitro mixed lymphocyte reaction showed that LEW responders presented a stronger proliferative response to BN stimulators compared with the BN responders to LEW stimulators, 22 which may be one explanation for the relatively higher occurrence of GvHD in the LEW-to-BN combination than in the BN-to-LEW combination.…”

Difficulties, guidelines and review of developing an acute rejection model after rat intestinal transplantation

“…It is also important to consider the higher weight and strength of Lewis rats compared with BN rats of the same age, which are more labile and vulnerable, which is crucial to know when planning a difficult postoperative period. Based on previous studies, Ye et al described a similar GVHD model with ACI-Lewis combination rats, although they also did not provide details [76,[78][79][80][81][82][83].…”

Induction of tolerance to composite tissue allograft in a rat model

“…8,29 However, the relevance of overall multlineage chimerism itself has been debated. 30,31 Coexistence of donor-derived and recipient-derived lymphatic populations (chimerism) might be the cause of tolerance or just an effect, an epiphenomenon. 32 In other words, the conditioning regimen might favor the survival of a limited number of regulatory cells such as CD4þ CD25þ T lymphocytes.…”