Pig Hematopoietic Cell Chimerism in Baboons Conditioned With a Nonmyeloablative Regimen and Cd154 Blockade1

Abstract

These results suggest that there is no absolute barrier to pig hematopoietic cell engraftment in primates, and that this may be facilitated if the return of anti-Gal IgG can be prevented.

Achieving tolerance in pig-to-primate xenotransplantation: Reality or fantasy

“…Subsequent studies attempted to increase engraftment by raising the dose of progenitor cells administered through the use of cytokine-mobilized PBPC, achieving doses as high as 2–4 × 10 10 cells/kg following mobilization and pheresis [62,63]. Even after administration of these enormous doses of pig cells, they were generally detected in the baboon circulation for only 2–5 days, although one animal demonstrated a second appearance of pig cells in the circulation on days 16–21 [64].…”

Recent Progress in Tolerance Induction through Mixed Chimerism

“…Newly developing B cells could not be found in spleens of late chimeras, suggesting deletion and/or receptor editing [117]. Still, engraftment barriers across species are difficult and might be overcome via retroviral gene therapy [104, 118]. …”

Pig–to–Non-human Primate Heart Transplantation: Immunologic Progress Over 20 Years

“…[12][13][14] Based on experience of allotransplantation across the ABO blood group barrier (reviewed in Ref 15), particularly by Alexandre and colleagues, 16 in which depletion of Abs at the time of the organ transplant resulted in accommodation (graft survival in the presence of specific anti-donor Ab and complement), enormous efforts were expended to achieve accommodation by the initial immunoadsorption of anti-Gal Abs using immunoaffinity columns of various Gal-glycoconjugates. [17][18][19][20][21][22][23][24][25] Although anti-Gal Ab could be depleted completely by a course of plasmapheresis and immunoadsorption over the period of a few days, and although this protected the graft from HAR, return of preformed and/or elicited Ab inevitably led to AHXR (Table 2 and Figure 3). 19,22,26 Despite pharmacologic immunosuppressive therapy, graft survival could not be extended beyond 30 days.…”

“…Less morbidity was reported when co-stimulatory blockade was introduced. 21, 24,39 The fact that anti-non-Gal Abs were not adsorbed may have been detrimental, as subsequent in vitro laboratory studies have indicated that anti-non-Gal Abs can result in pig cell lysis. 41 It has recently been demonstrated that anti-non-Gal Abs can be associated with AHXR.…”

“…21,22,26 The introduction of co-stimulatory blockade allowed prevention of a T-cell-dependent elicited Ab response without the morbidity associated with intensive pharmacologic immunosuppressive therapy. Buhler et al 21,24 and Knosalla et al 45,46 administered anti-CD154 monoclonal Abs (in combination with MMF and corticosteroids) in a pig-hematopoietic-progenitor-cell-tobaboon transplantation model, and demonstrated the efficacy of this agent. Confirmation was demonstrated in a solid-organ transplant model, but again was limited by the continuing effect of pre-formed Ab (Table 3 and Figure 4).…”