We have, recently, discussed host engineering to avoid hyperacute rejection of pig organs. I made it clear that I'm not nuts about the concept, and that this is the one area where I feel that ALXN has a leg up over BTRN. Again, I hope and trust that the Imutran (Novartis) connection has the issue of donor engineering in hand. If not, here's the heroic effort devised by TBRC as an alternative approach. An analyst friend of mine, who hates xenotransplantation, recently remarked that he wished that ALXN would simply sell their xeno efforts to BTRN and/or Novartis. I think that this is a great idea. An abstract describing the Imutran approach follows the Sachs et al. stuff. Apologies if I've posted it previously......
Transplantation 1998 Jul 27;66(2):176-82
Anti-Gal(alpha)1-3Gal antibody response to porcine bone marrow in
unmodified baboons and baboons conditioned for tolerance induction.
Kozlowski T, Monroy R, Xu Y, Glaser R, Awwad M, Cooper DK, Sachs DH
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA.
BACKGROUND: Mixed lymphohematopoietic chimerism can provide an effective means of inducing longterm immunological
tolerance and has been documented in a monkey allograft model. A conditioning regimen including nonmyeloablative or
myeloablative irradiation and splenectomy has been used to induce chimerism in a pig-to-primate transplantation model. Since
the presence of anti-Gal(alpha)1-3Gal (alphaGal) natural antibodies leads to the hyperacute rejection of pig organs transplanted
into primates, extracorporeal immunoaffinity adsorption (EIA) of anti-alphaGal antibodies is also included in the regimen. The
effect of the tolerance induction protocol on the anti-alphaGal antibody response has been assessed. METHODS:
Anti-alphaGal antibody was measured after the EIA of plasma through an alphaGal immunoaffinity column in baseline studies
involving two unmodified baboons, one splenectomized baboon, and one baboon that received a challenge with porcine bone
marrow (BM), and in three groups of baboons (n=2 in each group) that received different conditioning regimens for tolerance
induction. Group 1 received a nonmyeloablative conditioning regimen without porcine BM transplantation. Group 2 received
nonmyeloablative conditioning with pig BM transplantation and pig cytokine therapy. Group 3 received myeloablative
conditioning, an autologous BM transplant (with BM depleted of CD2+ or CD2+/CD20+ cells), and pig BM transplantation.
RESULTS: In the baseline studies, a single EIA of anti-alphaGal antibodies in an unmodified animal initially depleted
anti-alphaGal antibody, followed by a mild rebound. Nonmyeloablative conditioning (group 1) in the absence of pig cell
exposure reduced the rate of anti-alphaGal antibody return. Pig BM cells markedly stimulated anti-alphaGal antibody
production in an unmodified baboon (alphaGal IgM and IgG levels increased 40- and 220-fold, respectively). This response
was significantly reduced (to an only 2- to 5.5-fold increase of IgM and IgG) in baboons undergoing nonmyeloablative
conditioning (group 2). A myeloablative conditioning regimen (group 3) prevented the antibody response to pig BM, with the
reduction in response being greater in the baboon that received autologous BM depleted of both CD2+ and CD20+ cells. No
new antibody directed against pig non-aGal antigens was detected in any baboon during the 1 month follow-up period.
CONCLUSIONS: (i) EIA of anti-alphaGal antibody in unmodified baboons results in a transient depletion followed by a mild
rebound of antibody; (ii) exposure to pig BM cells results in a substantial increase in anti-alphaGal antibody production; (iii) a
nonmyeloablative conditioning regimen reduces the rate of antibody return and (iv) markedly reduces the response to pig BM
cells; (v) the anti-alphaGal response is completely suppressed by a myeloablative regimen if CD2+ and CD20+ cells are
eliminated from the autologous BM inoculum. Furthermore, (vi) challenge with pig BM cells appears to stimulate only an
anti-alphaGal antibody response without the development of other (non-alphaGal) anti-pig antibodies. We conclude that
regimens used for T-cell tolerance induction can be beneficial in reducing the anti-alphaGal antibody response to porcine BM.
Transplantation 1998 Jun 27;65(12):1584-90
Life-supporting pig-to-primate renal xenotransplantation using genetically
modified donors.
Zaidi A, Schmoeckel M, Bhatti F, Waterworth P, Tolan M, Cozzi E, Chavez G, Langford G, Thiru S, Wallwork J,
White D, Friend P
Imutran Ltd (A Novartis Pharma AG Company); and Papworth Hospital, Cambridge, United Kingdom.
BACKGROUND: In order to circumvent the complement-mediated hyperacute rejection of discordant xenografts, a colony of
pigs transgenic for the human regulator of complement activity, human decay-accelerating factor (hDAF), has been produced.
METHODS: Seven kidneys from hDAF transgenic pigs and six kidneys from nontransgenic control pigs were transplanted into
cynomolgus monkeys; both native kidneys were removed during the same operation. The recipient animals were
immunosuppressed with cyclosporine, steroids, and cyclophosphamide. RESULTS: In the transgenic group, the median
survival time was 13 days (range, 6-35 days); the median survival time in the control group was 6.5 days (range, 0.3-30 days).
There were no cases of hyperacute rejection in the transgenic group, and the two longest-surviving kidneys in this group
showed no evidence of rejection on histological examination. In contrast, all control kidneys underwent antibody-mediated
rejection, one demonstrating hyperacute rejection and the others acute vascular rejection. CONCLUSION: This study
demonstrates that (i) a kidney from an hDAF transgenic pig can support the life of a primate for up to 35 days (and also shows
the basic physiological compatibility between the pig and nonhuman primate); (ii) nontransgenic kidneys are not routinely
hyperacutely rejected; and (iii) the presence of hDAF on the kidney confers some protection against acute vascular rejection.
Improved immunosuppression and immunological monitoring may enable extended survival. |
