Composite Tissue Allografts in Rats: IV. Graftversus-Host Disease in Recipients of Vascularized Bone Marrow Transplants

Abstract

This laboratory has used a composite tissue allograft model as a vehicle for studies on a new type of bone marrow transplant, the vascularized bone marrow transplant. The model consists of a rat hind limb transplant that incorporates integumentary musculoskeletal, and lymphopoietic tissues. These transplants, in comparison with conventional marrow transplants, have the advantage of providing a syngeneic microenvironment and immediate engraftment of both mature and progenitor hemopoietic cells at the time of transplantation. The characteristics of graft-versus-host disease were studied in this model. Lewis X Brown Norway F1 (LBN RT-1(1+n)) rats received hind limbs from Lewis (LEW RT-1(1)) donors (n = 19). Animals were observed daily for signs of graft-versus-host disease. Necropsies were performed. A minority of animals developed lethal disease (7 of 19 recipients) and demonstrated cachexia with concomitant histopathologic changes of the disease. Acute and chronic groups emerged with distinct clinical courses, which are similar to other models of this disease. Recipients of vascularized bone marrow transplants (limb transplants) showed clinical and histopathologic changes of the disease. The transplants may be used as a model of graft-versus-host disease in humans. Most interestingly, the transplant has a lower incidence of disease compared with other methods of bone marrow transplantation and represents an alternative to conventional bone marrow transplantation, which deserves further exploration. It may be possible to develop a new technique for bone marrow transplantation based on this surgical approach. It is proposed that the transfer of vascularized blocks of bone/marrow into prospective recipients as opposed to cellular bone marrow transplants may be preferable.

Immunologic Approaches to Composite Tissue Allograft

“…[82][83][84] This observation could be explained by the fact that a very small amount of active BM is expected to be transferred with this type of CTA. 79,80,85 Furthermore, since the first successful transplantation of BM in humans in 1968, 86 much progress has been made in clinical use as well as in experimental models to treat non-life-threatening conditions through hematopoietic reconstitution. The extension of lower-risk protocols, such as the "non-total body irradiation" approach, to establish the state of mixed chimerism across MHC barriers seems to be an important point to reduce the toxicity occurring from the conditioning of the host.…”

“…A possible disadvantage of transplanting a limb allograft with functional immune effector cells is the potential for these mature allogeneic T cells to attack the recipient's tissue, resulting in the serious clinical reaction GVHD. 79 In 1990, Hewitt et al used rat hind limb transplantation to evaluate the involvement of VBMT in inducing GVHD. They observed that approximately 35% to 40% of the recipients developed GVHD when parental Lewis rat hind limbs were transplanted to Lewis ϫ Brown Norway F1 hybrids.…”

“…Indeed, a low-level of mixed lymphocyte chimerism is associated with the induction of tolerance after limb transplantation, but unstable highlevel lymphocyte chimerism is associated with the development of GVHD, indicating that a very fine balance exists between tolerance and GVHD. 79 Then in 2003, the same group developed an isolated VBMT (iVBMT) model to study the contribution of the BM component in a CTA. The investigators demonstrated that it was not the vascularized BM within a CTA that caused the GVHD.…”

Past, present, and future research in the field of composite tissue allotransplantation

“…Numerous studies by our laboratory have used this VBMT model to demonstrate that the development of low-level, stable mixed lymphocyte chimerism after limb allografting is associated with alloimmune tolerance induction, while unstable, high-level lymphocyte chimerism is associated with the development of graft-versus-host disease (GVHD). 32,[74][75][76][77][78][79] The work of Lee and associates 80 in Boston concerning tolerance induction has also been instrumental in the field of CTA. They have been successful in inducing long-term tolerance to vascularized musculoskeletal allografts in major histocompatibility complex-matched, minor antigenmismatched pigs after only a 12-day postoperative course of cyclosporine A. Lee has also used intrathymic injection of donor-derived bone marrow cells along with the short-term use of an anti-lymphocyte serum to prolong survival of skin allografts in rats.…”

Chimerism induction in vascularized bone marrow transplants augmented with bone marrow cells

“…1,2,13-15 A microsurgically transplanted hind limb allograft contains bone marrow tissue, which is an immunomodulatory factor that facilitates allograft tolerance 15,16 ; the allograft also contains lymph nodes, neurovascular structures, muscle, cartilage, tendon, ligament, and skin, which is accepted as the most antigenic tissue of the body. 17,18 Allogeneic hind limb transplantation is technically complex and leaves the recipient with a functional deformity.…”