A. Aitouche

Augmentation of chimerism with perioperative donor bone marrow infusion in organ transplant recipients: A 44 month follow-up☆

A.S. Rao, P. Fontes, A. Iyengar, R. Shapiro, F. Dodson, R. Corry, S. Pham, M. Jordan, A. Zeevi, C. Rastellini, A. Aitouche, F. Egidi, H.A. Gritsch, J. Reyes, J.J. Fung, and T.E. Starzl Thomas E. Starzl Transplantation Institute and the Departments of Surgery (A.S.R., P.F., A.I., R.S., F.D., R.C., S.P., M.J., C.R., J.R., J.J.F., T.E.S.) and Pathology (A.S.R., A.Z.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Combined blockade of CD28/B7 and CD40/CD40L costimulatory pathways prevents the onset of chronic rejection

Signaling through CD28/B7 and CD40/CD40L co-stimulatory pathways as a prerequisite for optimal T-cell activation has been well documented.1,2 Furthermore, unlike that through CD40/gp39, blockade of signaling through the CD28/B7 pathway by perioperative use of CTLA4-Ig fusion protein has been shown to enhance allograft survival and mitigate the development of chronic rejection (CR).3 In contrast, combined blockage of these two pathways has been shown to abrogate the development of posttransplant vasculopathy in a murine model of cardiac allotransplantation.1 However, the utility of this latter model to study pathogenesis of CR is limited and, for its acceptance and mitigation of acute cellular rejection, the use of immunosuppressive drugs is required—agents themselves implicated in playing a role in the etiopathology of this lesion. It is for this purpose that we have developed an aortic allotransplantation (AOTx) model of CR in mice in which, for the acceptance of the graft, no immunosuppression is required and in which resultant changes established within 30 days posttransplantation are pathognomonic of CR.4 Reported herein is the role of blockade of costimulation and the evolution of CR.

Immune modulation in organ allograft recipients by single or multiple donor bone marrow infusions

The discovery of persistent alloantigen (i.e., chimerism) in the lymphoid and nonlymphoid tissues of successful long-term organ transplant recipients has prompted many to conclude that this phenomenon plays an important role in allograft acceptance.1,2 These findings have been corroborated in experimental models of transplantation (Tx) tolerance.3 Although the precise phenotype of cells involved in the induction of observed donor-specific tolerance (DST) is unclear, there exists overwhelming evidence suggesting that perhaps immature dendritic cells, which are resident within the graft and known to migrate after Tx, modulate host anti-donor effector responses.4 As these cells are of bone marrow (BM) origin, it was rational to propose that perioperative donor BM infusion may augment this phenomenon with resultant salutary effect on patient and graft survivals. In 1992 we initiated a clinical trial involving perioperative infusion of unmodified BM cells obtained from the vertebral bodies of cadaveric donors into abdominal and thoracic organ allograft recipients. An interim analysis of the outcome in these patients is reported at their most recent follow-up.

Endothelin-1 receptor blockade and its effect on chronic rejection

ENDOTHELIN-l (ET-l), a 21 amino acid peptide with potent vasoconstrictive properties has been implicated in the development of acute allograft rejection.) It is primarily produced by endothelial cells and its secretion, during acute rejection episodes, has been shown to be upregulated by TGFf3 and other proinflammatory cytokines released by graft infiltrating cells.) Additionally, ET-l has also been shown to facilitate proliferation of a-smooth muscle actin-positive (a-smA +) cells? Given that proliferation and/or accumulation of a-smA + cells is a prominent feature in neointimal thickening encountered in posttransplant vasculopathy, it is rational to propose that ET-l may play an important role in the pathogenesis of this lesion. To test this tenet, we proceeded to block ET-receptors (both ETA and ET B) by bosentan (a non peptide antagonist of ET -1) and to study its influence on the evolvement of chronic rejection (CR) in an established mouse model of aortic allotransplantation.3

The role of Fas/FasL apoptotic pathway in the development of chronic rejection.

FAS (CD95), a member of the tumor necrosis factor-receptor family is universallv expressed on various tissues of the body.1 On the contrary. its ligand (Fas L) has a more restricted pattern of expression being found predominantly on activated T cells and on discrete cells in the eye and in the testis.2 It has been recently shown that the interaction between Fas and FasL plays an important role in inducing apoptotic cell death.3 Furthermore. interactions of these molecules have also been shown to mediate tissue destruction witnessed during acute cellular rejection (ACR) of organ allografts.4 This latter finding has prompted many to evolve novel therapeutic strategies aimed at interrupting Fas/FasL binding to mitigate or abrogate AC R. However. the role of Fas system in the pathogenesis of chronic rejection (CR) is as yet undetermined. To address this issue, FasL-deficient mice were used as donor and/or recipients of aortic allografts: reported herein is the out-come of this study.

Mechanisms underlying the development of T-cell tolerance following interruption of signalling at the CD28/B7 and CD40/gp39 interface.

C. Rastellini, A. Salam, R. Kuddus, A. Aitouche, M. Braun, R. Leach, R. Peach, J.J. Fung, T.E. Starzl, and A.S. Rao Section of Cellular Transplantation, Thomas E. Starzl Transplantation Institute and the Departments of Surgery (C.R., A.S., R.K., A.A., M.B., R.L., J.J.F., T.E.S., A.S.R.) and Pathology (A.S.R.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Bristol-Myers Squibb (R.P.), Inc, Princeton, New Jersey.

Documentation in Bone-Marrow-Augmented Organ Recipients of the Presence of Dendritic Cell Progenitors of Donor Origin

The ubiquitous presence of donor cell chimerism in the tissues of long-term successful organ allograft recipients1–3 provided quintessential support to the argument that these cells play a seminal role in allograft acceptance and in the induction of donor-specific tolerance. A finding of commensurate significance was the observation that livers (unlike other organs) when transplanted orthotopically across most mouse4 and several rat-strain combinations5,6 and in few outbred pigs7,8 are spontaneously accepted without the necessity for exogenous immunosuppression. This ascertainment complemented by the novel observations made by Lu et al9 has prompted the advancement of the hypothesis that perhaps the comparative tolerogenicity of various organs is contingent on the quantity and quality of resident migratory cells, of which those of dendritic leukocyte lineage conceivably play an auspicious role. Given their functional significance, we initiated a systematic search to establish the presence of progenitors of donor-dendritic cells (DC) in the peripheral blood of bone marrow (BM)-augmented organ transplant recipients. Additionally, the evidence for the multilineage donor cell chimerism was also sought; reported herein is the outcome of these investigations.