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1. Surgical outcome in diffuse low-grade glioma - contemporary prospective data from the LoG-Glio registry

Author

Coburger, J, Rückriegel, S, Nadji-Ohl, M, von der Brelie, C, Roder, C, Faust, K, Sachs, D, Löhr, M, Grüninger, S, Vajkoczy, P, Tatagiba, M, Ernestus, RI, Rohde, V, Ganslandt, O, Wirtz, CR, Pala, A, Coburger, J, Rückriegel, S, Nadji-Ohl, M, von der Brelie, C, Roder, C, Faust, K, Sachs, D, Löhr, M, Grüninger, S, Vajkoczy, P, Tatagiba, M, Ernestus, RI, Rohde, V, Ganslandt, O, Wirtz, CR, and Pala, A

Published
2020

2. Contemporary management of diffuse low-grade glioma from six certified neuro-oncological centres - prospective data from the LoG-Glio registry

Author

Coburger, J, Nadji-Ohl, M, von der Brelie, C, Rückriegel, S, Roder, C, Faust, K, Sachs, D, Grüninger, S, Löhr, M, Vajkoczy, P, Tatagiba, M, Ernestus, RI, Rohde, V, Ganslandt, O, Wirtz, CR, Pala, A, Coburger, J, Nadji-Ohl, M, von der Brelie, C, Rückriegel, S, Roder, C, Faust, K, Sachs, D, Grüninger, S, Löhr, M, Vajkoczy, P, Tatagiba, M, Ernestus, RI, Rohde, V, Ganslandt, O, Wirtz, CR, and Pala, A

Published
2020

3. Surgical outcome in diffuse low-grade glioma - contemporary prospective data from the LoG-Glio registry

Author

Coburger, J, Rückriegel, S, Nadji-Ohl, M, von der Brelie, C, Roder, C, Faust, K, Sachs, D, Löhr, M, Grüninger, S, Vajkoczy, P, Tatagiba, M, Ernestus, RI, Rohde, V, Ganslandt, O, Wirtz, CR, Pala, A, Coburger, J, Rückriegel, S, Nadji-Ohl, M, von der Brelie, C, Roder, C, Faust, K, Sachs, D, Löhr, M, Grüninger, S, Vajkoczy, P, Tatagiba, M, Ernestus, RI, Rohde, V, Ganslandt, O, Wirtz, CR, and Pala, A

Published
2020

4. Contemporary management of diffuse low-grade glioma from six certified neuro-oncological centres - prospective data from the LoG-Glio registry

Author

Coburger, J, Nadji-Ohl, M, von der Brelie, C, Rückriegel, S, Roder, C, Faust, K, Sachs, D, Grüninger, S, Löhr, M, Vajkoczy, P, Tatagiba, M, Ernestus, RI, Rohde, V, Ganslandt, O, Wirtz, CR, Pala, A, Coburger, J, Nadji-Ohl, M, von der Brelie, C, Rückriegel, S, Roder, C, Faust, K, Sachs, D, Grüninger, S, Löhr, M, Vajkoczy, P, Tatagiba, M, Ernestus, RI, Rohde, V, Ganslandt, O, Wirtz, CR, and Pala, A

Published
2020

5. Corrections to Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection. (Immunity 44, 46-58, January 19, 2016).

Author

Heaton, NS, Heaton, NS, Moshkina, N, Fenouil, R, Gardner, TJ, Aguirre, S, Shah, PS, Zhao, N, Manganaro, L, Hultquist, JF, Noel, J, Sachs, D, Hamilton, J, Leon, PE, Chawdury, A, Tripathi, S, Melegari, C, Campisi, L, Hai, R, Metreveli, G, Gamarnik, AV, García-Sastre, A, Greenbaum, B, Simon, V, Fernandez-Sesma, A, Krogan, NJ, Mulder, LCF, van Bakel, H, Tortorella, D, Taunton, J, Palese, P, Marazzi, I, Heaton, NS, Heaton, NS, Moshkina, N, Fenouil, R, Gardner, TJ, Aguirre, S, Shah, PS, Zhao, N, Manganaro, L, Hultquist, JF, Noel, J, Sachs, D, Hamilton, J, Leon, PE, Chawdury, A, Tripathi, S, Melegari, C, Campisi, L, Hai, R, Metreveli, G, Gamarnik, AV, García-Sastre, A, Greenbaum, B, Simon, V, Fernandez-Sesma, A, Krogan, NJ, Mulder, LCF, van Bakel, H, Tortorella, D, Taunton, J, Palese, P, and Marazzi, I

Published
2016

6. Use of a spatially explicit individual-tree model (SORTIE/BC) to explore the implications of patchiness in structurally complex forests

Author

Coates, K. D., Canham, C.D., Beaudet, M., Sachs, D. L., Messier, C, Coates, K. D., Canham, C.D., Beaudet, M., Sachs, D. L., and Messier, C

Abstract

The discipline of silviculture is evolving rapidly, moving from an agricultural model that emphasized simple stand structures toward a natural disturbance- or ecosystem-based model where stands are managed for multiple species and complex structures. Predicting stand dynamics and future yields in mixed-species complex structured stands cannot be easily accomplished with traditional field experiments. We outline the development and structure of SORTIE/BC, a descendent of the SORTIE model. SORTIE/BC is a light-mediated, spatially explicit, mixed-species forest model that makes population dynamic forecasts for juvenile and adult trees. We use the model to simulate partial cutting prescriptions in temperate deciduous, boreal and temperate coniferous mixed-species forests. The species, amount and spatial pattern of canopy tree removal had a major influence on understory light environments. Low and uniform removal of canopy trees were less successful in favouring the growth and survival of regenerating trees of intermediate to shade intolerant species and the growth of retained canopy trees than patch removal. In the boreal mixedwood, strip-cutting can maintain mixed stands but careful attention must be paid to buffer and strip management to optimize stand growth. We conclude that SORTIE/ BC can be very useful to explore and explain the silvicultural implications of complex silvicultural prescriptions for which there are no existing long-term experiments. © 2003 Elsevier B.V. All rights reserved.

Published
2003

7. Adult porcine islet transplantation in baboons treated with conventional immunosuppression or a non-myeloablative regimen and CD154 blockade.

Author

UCL - MD/MNOP - Département de morphologie normale et pathologique, UCL - MD/CHIR - Département de chirurgie, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de chirurgie et transplantation abdominale, Bühler, L, Deng, S, O'Neil, J, Kitamura, H, Koulmanda, M, Baldi, A, Rahier, Jacques, Alwayn, I P J, Appel, J Z, Awwad, M, Sachs, D H, Weir, G, Squifflet, Jean-Paul, Cooper, D K C, Morel, Ph, UCL - MD/MNOP - Département de morphologie normale et pathologique, UCL - MD/CHIR - Département de chirurgie, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de chirurgie et transplantation abdominale, Bühler, L, Deng, S, O'Neil, J, Kitamura, H, Koulmanda, M, Baldi, A, Rahier, Jacques, Alwayn, I P J, Appel, J Z, Awwad, M, Sachs, D H, Weir, G, Squifflet, Jean-Paul, Cooper, D K C, and Morel, Ph

Abstract

The aim of the present study was to assess the survival of adult porcine islets transplanted into baboons receiving either (I) conventional triple drug immunosuppressive therapy or (2) a non-myeloablative regimen and an anti-CD154 monoclonal antibody (mAb) aimed at tolerance-induction. Group 1 baboons (n = 3) were pancreatectomized prior to intraportal injection of 10,000 porcine islet equivalents (IE)/kg and immunosuppressed with anti-thymocyte globulin (ATG), cyclosporine and azathioprine. In Group 2 (n = 2), non-pancreatectomized baboons underwent induction therapy with whole body and thymic irradiation, and ATG. Extracorporeal immunoadsorption (EIA) of anti-Galalpha1,3Gal (Gal) antibody was carried out. Maintenance therapy was with cobra venom factor, cyclosporine. mycophenolate mofetil, methylprednisolone and anti-CD154 mAb. Porcine islets were injected intraportally (14,000 and 32,000 IE/kg, respectively) and high-dose pig mobilized peripheral blood progenitor cells (3 x 10(10) cells/kg) were infused into a systemic vein. Porcine islets were also implanted in the sternomastoid muscle to facilitate subsequent biopsies. In both groups. porcine C-peptide was measured, and histological examination of liver or sternomastoid muscle biopsies was performed at regular intervals. In Group 1, total pancreatectomy reduccd human C-peptide to < 0.1 ng/ml and induced insulin-requiring diabetes. The transplantation of porcine islets was followed by normalization of glycemia for 15-24 h. Porcine C-peptide was detected only transiently immediately after porcine islet injection (maximum 0.12 ng/ml). Histological examination of liver biopsies taken between days 2 and 19 did not reveal viable islets, but necrotic cell structures with mononuclear cell infiltrates were identified in portal venules. In Group 2, injection of porcine islets into non-pancreatectomized recipients induced a transient hypoglycemia (2-4 h) requiring concentrated intravenous dextrose administration. Porcine

Published
2002

8. Long-term discordant xenogeneic (porcine-to-primate) bone marrow engraftment in a monkey treated with porcine-specific growth factors.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Sablinski, T, Emery, D W, Monroy, R, Hawley, R J, Xu, Y., Gianello, Pierre, Lorf, T, Kozlowski, T, Bailin, M, Cooper, D K, Cosimi, A B, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Sablinski, T, Emery, D W, Monroy, R, Hawley, R J, Xu, Y., Gianello, Pierre, Lorf, T, Kozlowski, T, Bailin, M, Cooper, D K, Cosimi, A B, and Sachs, D H

Abstract

BACKGROUND: Mixed allogeneic hematopoietic chimerism has previously been reliably achieved and shown to induce tolerance to fully MHC-mismatched allografts in mice and monkeys. However, the establishment of hematopoietic chimerism has been difficult to achieve in the discordant pig-to-primate xenogeneic model. METHODS: To address this issue, two cynomolgus monkeys were conditioned by whole body irradiation (total dose 300 cGy) 6 and 5 days before the infusion of pig bone marrow (BM). Monkey anti-pig natural antibodies were immunoadsorbed by extracorporeal perfusion of monkey blood through a pig liver, immediately before the intravenous infusion of porcine BM (day 0). Cyclosporine was administered for 4 weeks and 15-deoxyspergualin for 2 weeks. One monkey received recombinant pig cytokines (stem cell factor and interleukin 3) for 2 weeks, whereas the other received only saline as a control. RESULTS: Both monkeys recovered from pancytopenia within 4 weeks of whole body irradiation. Anti-pig IgM and IgG antibodies were successfully depleted by the liver perfusion but returned to pretreatment levels within 12-14 days. Methylcellulose colony assays at days 180 and 300 revealed that about 2% of the myeloid progenitors in the BM of the cytokine-treated recipient were of pig origin, whereas no chimerism was detected in the BM of the untreated control monkey at similar times. The chimeric animal was less responsive by mixed lymphocyte reaction to pig-specific stimulators than the control monkey and significantly hyporesponsive when compared with a monkey that had rejected a porcine kidney transplant. CONCLUSION: To our knowledge, this is the first report of long-term survival of discordant xenogeneic BM in a primate recipient.

Published
1999

9. Role of the thymus in transplantation tolerance in miniature swine. III. Surgical manipulation of the thymus interferes with stable induction of tolerance to class I-mismatched renal allografts.

Author

Harvard Medical School - Transplantation biology research center, MGH, Boston, Yamada, K, Ierino, F L, Gianello, Pierre, Shimizu, A, Colvin, R B, Sachs, D H, Harvard Medical School - Transplantation biology research center, MGH, Boston, Yamada, K, Ierino, F L, Gianello, Pierre, Shimizu, A, Colvin, R B, and Sachs, D H

Abstract

Previous studies have demonstrated that long-term tolerance of class I mismatched renal allografts in miniature swine is induced by a short course of cyclosporine (CyA), and that a total thymectomy 21 days before transplantation abrogates the induction of stable tolerance. We have now examined the effects of surgical manipulation of the thymus, with or without a reduction in the thymic volume, on the induction of tolerance.

Published
1999

10. Role of the thymus in transplantation tolerance in miniature swine: II. Effect of steroids and age on the induction of tolerance to class I mismatched renal allografts.

Author

Harvard Medical School - Transplantation biology research center, MGH, Boston, Yamada, K, Gianello, Pierre, Ierino, F L, Fishbein, J, Lorf, T, Shimizu, A, Colvin, R B, Sachs, D H, Harvard Medical School - Transplantation biology research center, MGH, Boston, Yamada, K, Gianello, Pierre, Ierino, F L, Fishbein, J, Lorf, T, Shimizu, A, Colvin, R B, and Sachs, D H

Abstract

Recent studies in young (5-7 months) miniature swine have demonstrated that the thymus is involved in the rapid induction of stable tolerance to class I mismatched renal allografts after a 12-day course of Cyclosporine (CyA). Because both steroids and age are known to influence the structure and function of the thymus, we have now studied the effects of these two parameters on tolerance induction in this model.

Published
1999

11. Long-term outcome and alloantibody production in a non-myeloablative regimen for induction of renal allograft tolerance.

Author

Massachusetts General Hospital, Boston 02114, USA - Department of Surgery, Harvard Medical School, Kawai, T, Poncelet, Alain, Sachs, D H, Mauiyyedi, S, Boskovic, S, Wee, S L, Ko, D S, Bartholomew, A, Kimikawa, M, Hong, H Z, Abrahamian, G, Colvin, R B, Cosimi, A B, Massachusetts General Hospital, Boston 02114, USA - Department of Surgery, Harvard Medical School, Kawai, T, Poncelet, Alain, Sachs, D H, Mauiyyedi, S, Boskovic, S, Wee, S L, Ko, D S, Bartholomew, A, Kimikawa, M, Hong, H Z, Abrahamian, G, Colvin, R B, and Cosimi, A B

Abstract

Multilineage chimerism and long-term acceptance of renal allografts has been produced in non-human primates conditioned with a nonmyeloablative regimen. Our study was undertaken to evaluate the immunological and pathological status of long-term survivors and to define the role of splenectomy and of the primarily vascularized kidney in the regimen. Monkeys were treated with the basic regimen, including: total body irradiation, thymic irradiation, antithymocyte globulin, donor bone marrow transplantation, and a 4-week course of cyclosporine after which no further immunosuppression was given. They were divided into four groups according to the timing of kidney transplantation (KTx) and splenectomy as follows; group A (n=13): KTx and splenectomy on the day of donor bone marrow transplantation (day 0); group B (n=3): KTx on day 0 without splenectomy; group C (n=7): splenectomy on day 0 but delayed KTx until 3 to 16 weeks post-donor bone marrow transplantation; group D (n=3): both splenectomy and KTx delayed until day 120 post-donor bone marrow transplantation. In group A, 11 of 13 monkeys developed chimerism and 9 monkeys achieved long-term survival of 4 to 70 months without evidence of chronic vascular rejection. Alloantibodies were detected in only one long-term survivor. In contrast, all three monkeys in group B developed alloantibodies and rejected their allografts. In group C, long-term survival without alloantibody production was observed in two of three monkeys that had developed chimerism. In group D, all three recipients were sensitized and rejected the kidney allografts rapidly after transplantation. 1) Production of anti-donor antibody was prevented in most recipients that developed mixed chimerism in the regimens with splenectomy at the time of donor bone marrow transplantation. 2) If splenectomy is not included in the initial conditioning regimen, induction of B cell tolerance is less likely and the result is late onset of alloantibody production and allogra

Published
1999

12. Removal of anti-porcine natural antibodies from human and nonhuman primate plasma in vitro and in vivo by a Galalpha1-3Galbeta1-4betaGlc-X immunoaffinity column.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Xu, Y., Lorf, T, Sablinski, T, Gianello, Pierre, Bailin, M, Monroy, R, Kozlowski, T, Awwad, M, Cooper, D K, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Xu, Y., Lorf, T, Sablinski, T, Gianello, Pierre, Bailin, M, Monroy, R, Kozlowski, T, Awwad, M, Cooper, D K, and Sachs, D H

Abstract

BACKGROUND: Natural antibodies (NAbs) against a terminal alpha1-3 galactosyl (alphaGal) epitope have been identified as the major human anti-pig NAbs. METHODS AND RESULTS: We used two synthetic alphaGal trisaccharides--type 6 (alphaGal6) and type 2(alphaGal2)--linked to an inert matrix to remove NAbs from human plasma in vitro. Flow cytometry indicated that an average of 85% of the NAb binding activity was depleted by adsorption with alphaGal6. By measuring the binding of NAbs to pig peripheral blood mononuclear cells and bone marrow cells, we demonstrated that alphaGal6 was more effective than alphaGal2 in removing NAbs, and the combination of alphaGal6 + alphaGal2 did not further increase removal of NAbs. The specificity of the removal of NAbs (IgM and IgG) reactive with the alphaGal epitope by alphaGal6 matrix was shown by enzyme-linked immunosorbent assay. In vivo studies in nonhuman primates compared plasma perfusion through a alphaGal6 immunoaffinity column with hemoperfusion through a pig liver for changes in blood pressure, hematocrit, platelets, and NAb adsorption. CONCLUSIONS: Both methods reduced the level of anti-pig IgM and IgG xenoreactive antibodies to nearly background, but column perfusion caused less hypotension and reduction in platelets than liver perfusion. Four pig kidneys transplanted into monkeys after column perfusion did not undergo hyperacute rejection, remaining functional for 2-10 days, with a mean functional period of 7 days, demonstrating that a pig kidney can support renal function in a primate.

Published
1998

13. Demonstration of multilineage chimerism in a nonhuman primate concordant xenograft model.

Author

Massachusetts General Hopital,Harvard Medical School, Boston, Massachusetts - Department of Surgery, Ko, D S, Bartholomew, A, Poncelet, Alain, Sachs, D H, Huang, C, LeGuern, A, Abraham, K I, Colvin, R B, Boskovic, S, Hong, H Z, Wee, S L, Winn, H J, Cosimi, A B, Massachusetts General Hopital,Harvard Medical School, Boston, Massachusetts - Department of Surgery, Ko, D S, Bartholomew, A, Poncelet, Alain, Sachs, D H, Huang, C, LeGuern, A, Abraham, K I, Colvin, R B, Boskovic, S, Hong, H Z, Wee, S L, Winn, H J, and Cosimi, A B

Abstract

Prior studies from our laboratory have demonstrated that a nonmyeloablative conditioning regimen can induce transient mixed chimerism and renal allograft tolerance between MHC disparate cynomolgus monkeys. We have also shown that this preparative regimen can be extended to a concordant baboon to cynomolgus xenograft model by adding, to the post transplant protocol, therapy designed to prevent antibody production. Here we examine the use of brequinar (BQR) for this purpose and the efficacy of two new reagents developed to demonstrate the establishment of chimerism in the xenograft recipients. The cynomolgus recipients were conditioned with WBI (300 cGy), TI (700 cGy), ATG, cyclosporine, and brequinar sodium. To detect engraftment of the donor marrow, we prepared a polyclonal cynomolgus anti-baboon antibody (CABA) and a monoclonal antibody (215.1), which distinguish baboon and cynomolgus lymphocytes and granulocytes. We employed flow cytometry analysis to detect multilineage chimerism in the xenograft recipients. Five of the six recipients monitored using our new reagents (CABA and 215.1) developed detectable chimerism and only one of these animals lost its kidney to rejection. However, other complications have not permitted assessment of long-term outcome. The features of the multilineage chimerism included the detection of donor granulocytes (1.8-77.4%) and lymphocytes (2.4-22.2%) for 9 to 37 days. Our new reagents permit the detection of multilineage mixed chimerism, which may be a predictor of xenograft tolerance. We also conclude that brequinar may be effective in preventing antibody formation, but because of its toxicity, it is probably not the drug of choice for extension of the mixed chimerism protocol to concordant xenografts.

Published
1998

14. Analysis of the immunological cross reactivities of 213 well characterized monoclonal antibodies with specificities against various leucocyte surface antigens of human and 11 animal species

Author

Brodersen, R., Bijlsma, F., Gori, K., Jensen, K. T., Chen, W., Dominguez, J., Haverson, K., Moore, P. F., Saalmüller, A., Sachs, D. H., Slierendrecht, W. J., Stokes, C. R., Vainio, O., Zuckermann, F. A., Aasted, B., Brodersen, R., Bijlsma, F., Gori, K., Jensen, K. T., Chen, W., Dominguez, J., Haverson, K., Moore, P. F., Saalmüller, A., Sachs, D. H., Slierendrecht, W. J., Stokes, C. R., Vainio, O., Zuckermann, F. A., and Aasted, B.

Published
1998

15. Analyses of monoclonal antibodies reacting with porcine CD5:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Tomaskovic, M., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Saalmüller, A., Aasted, B., Pescovitz, M. D., Book, B. K., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Tomaskovic, M., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Saalmüller, A., and Aasted, B.

Published
1998

16. Analyses of monoclonal antibodies reacting with porcine CD3:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Lackovic, G., Kirkham, P., Parkhouse, R. M. E., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Lackovic, G., Kirkham, P., Parkhouse, R. M. E., and Saalmüller, A.

Published
1998

17. Report on the analyses of mAb reactive with porcine CD8 for the 2. International Swine CD Workshop

Author

Zuckermann, F. A., Pescovitz, M. D., Aasted, B., Dominguez, J., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W. C., Barbosa, I. R., Saalmüller, A., Zuckermann, F. A., Pescovitz, M. D., Aasted, B., Dominguez, J., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W. C., Barbosa, I. R., and Saalmüller, A.

Published
1998

18. Analyses of monoclonal antibodies reacting with porcine wCD6:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Petrinec, N., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Petrinec, N., and Saalmüller, A.

Published
1998

19. Summary of the first round analyses of the 2. International Swine CD Workshop

Author

Saalmüller, A., Pauly, T., Aasted, B., Jensen, K. T., Sachs, D. H., Nielsen, J., Arn, S., Davis, W. C., Park, Y. H., McCullough, K., Summerfield, A., Murtaugh, M., Pampusch, M. S., Burger, K. D., Laber, J., Pescovitz, M. D., Stokes, C. R., Haverson, K., Boyd, P. C., Lunney, J. K., Saalmüller, A., Pauly, T., Aasted, B., Jensen, K. T., Sachs, D. H., Nielsen, J., Arn, S., Davis, W. C., Park, Y. H., McCullough, K., Summerfield, A., Murtaugh, M., Pampusch, M. S., Burger, K. D., Laber, J., Pescovitz, M. D., Stokes, C. R., Haverson, K., Boyd, P. C., and Lunney, J. K.

Published
1998

20. Summary of workshop findings for antibodies reacting with porcine T-cells and activation antigens:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Sver, L., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W., Barbosa, I. R., Zuckermann, F. A., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Sver, L., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W., Barbosa, I. R., Zuckermann, F. A., and Saalmüller, A.

Published
1998

21. Immunoprecipitation studies of monoclonal antibodies submitted to the 2. International Swine CD Workshop

Author

Aasted, B., Gori, K., Dominguez, J., Ezquerra, A., Bullido, R., Arn, S., Bianchi, A., Binns, R. M., Chu, R. M., Davis, W. C., Denham, S., Haverson, K., Jensen, K. T., Kim, Y. B., Magyar, A., Petersen, K. R., Saalmüller, A., Sachs, D. H., Schütt, C., Shimizu, M., Stokes, C. R., Whitfall, T., Yang, H., Zuckermann, F. A., Aasted, B., Gori, K., Dominguez, J., Ezquerra, A., Bullido, R., Arn, S., Bianchi, A., Binns, R. M., Chu, R. M., Davis, W. C., Denham, S., Haverson, K., Jensen, K. T., Kim, Y. B., Magyar, A., Petersen, K. R., Saalmüller, A., Sachs, D. H., Schütt, C., Shimizu, M., Stokes, C. R., Whitfall, T., Yang, H., and Zuckermann, F. A.

Published
1998

22. Overview of the Second International Workshop to define swine cluster of differentiation (CD) antigens

Author

Saalmüller, A., Pauly, T., Lunney, J. K., Boyd, P. C., Aasted, B., Sachs, D. H., Arn, S., Bianchi, A., Binns, R. M., Licence, S., Whyte, A., Blecha, A., Chen, Z., Chu, R. M., Davis, W. C., Denham, S., Yang, H., Whittall, T., Parkhouse, R. M. E., Dominguez, J., Ezquerra, A., Alonso, F., Horstick, G., Howard, C., Sopp, P., Kim, Y. B., Lipp, J., Mackay, C., Magyar, A., McCullough, K., Arriens, A., Summerfield, A., Murtaugh, M., Nielsen, J., Novikov, B., Pescovitz, M. D., Schuberth, H. J., Leibold, W., Schütt, C., Saalmüller, A., Pauly, T., Lunney, J. K., Boyd, P. C., Aasted, B., Sachs, D. H., Arn, S., Bianchi, A., Binns, R. M., Licence, S., Whyte, A., Blecha, A., Chen, Z., Chu, R. M., Davis, W. C., Denham, S., Yang, H., Whittall, T., Parkhouse, R. M. E., Dominguez, J., Ezquerra, A., Alonso, F., Horstick, G., Howard, C., Sopp, P., Kim, Y. B., Lipp, J., Mackay, C., Magyar, A., McCullough, K., Arriens, A., Summerfield, A., Murtaugh, M., Nielsen, J., Novikov, B., Pescovitz, M. D., Schuberth, H. J., Leibold, W., and Schütt, C.

Published
1998

23. Analysis of the immunological cross reactivities of 213 well characterized monoclonal antibodies with specificities against various leucocyte surface antigens of human and 11 animal species

Author

Brodersen, R., Bijlsma, F., Gori, K., Jensen, K. T., Chen, W., Dominguez, J., Haverson, K., Moore, P. F., Saalmüller, A., Sachs, D. H., Slierendrecht, W. J., Stokes, C. R., Vainio, O., Zuckermann, F. A., Aasted, B., Brodersen, R., Bijlsma, F., Gori, K., Jensen, K. T., Chen, W., Dominguez, J., Haverson, K., Moore, P. F., Saalmüller, A., Sachs, D. H., Slierendrecht, W. J., Stokes, C. R., Vainio, O., Zuckermann, F. A., and Aasted, B.

Published
1998

24. Analyses of monoclonal antibodies reacting with porcine wCD6:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Petrinec, N., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Petrinec, N., and Saalmüller, A.

Published
1998

25. Analyses of monoclonal antibodies reacting with porcine CD3:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Lackovic, G., Kirkham, P., Parkhouse, R. M. E., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Lackovic, G., Kirkham, P., Parkhouse, R. M. E., and Saalmüller, A.

Published
1998

26. Overview of the Second International Workshop to define swine cluster of differentiation (CD) antigens

Author

Saalmüller, A., Pauly, T., Lunney, J. K., Boyd, P. C., Aasted, B., Sachs, D. H., Arn, S., Bianchi, A., Binns, R. M., Licence, S., Whyte, A., Blecha, A., Chen, Z., Chu, R. M., Davis, W. C., Denham, S., Yang, H., Whittall, T., Parkhouse, R. M. E., Dominguez, J., Ezquerra, A., Alonso, F., Horstick, G., Howard, C., Sopp, P., Kim, Y. B., Lipp, J., Mackay, C., Magyar, A., McCullough, K., Arriens, A., Summerfield, A., Murtaugh, M., Nielsen, J., Novikov, B., Pescovitz, M. D., Schuberth, H. J., Leibold, W., Schütt, C., Saalmüller, A., Pauly, T., Lunney, J. K., Boyd, P. C., Aasted, B., Sachs, D. H., Arn, S., Bianchi, A., Binns, R. M., Licence, S., Whyte, A., Blecha, A., Chen, Z., Chu, R. M., Davis, W. C., Denham, S., Yang, H., Whittall, T., Parkhouse, R. M. E., Dominguez, J., Ezquerra, A., Alonso, F., Horstick, G., Howard, C., Sopp, P., Kim, Y. B., Lipp, J., Mackay, C., Magyar, A., McCullough, K., Arriens, A., Summerfield, A., Murtaugh, M., Nielsen, J., Novikov, B., Pescovitz, M. D., Schuberth, H. J., Leibold, W., and Schütt, C.

Published
1998

27. Summary of the first round analyses of the 2. International Swine CD Workshop

Author

Saalmüller, A., Pauly, T., Aasted, B., Jensen, K. T., Sachs, D. H., Nielsen, J., Arn, S., Davis, W. C., Park, Y. H., McCullough, K., Summerfield, A., Murtaugh, M., Pampusch, M. S., Burger, K. D., Laber, J., Pescovitz, M. D., Stokes, C. R., Haverson, K., Boyd, P. C., Lunney, J. K., Saalmüller, A., Pauly, T., Aasted, B., Jensen, K. T., Sachs, D. H., Nielsen, J., Arn, S., Davis, W. C., Park, Y. H., McCullough, K., Summerfield, A., Murtaugh, M., Pampusch, M. S., Burger, K. D., Laber, J., Pescovitz, M. D., Stokes, C. R., Haverson, K., Boyd, P. C., and Lunney, J. K.

Published
1998

28. Analyses of monoclonal antibodies reacting with porcine CD5:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Tomaskovic, M., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Saalmüller, A., Aasted, B., Pescovitz, M. D., Book, B. K., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Tomaskovic, M., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Saalmüller, A., and Aasted, B.

Published
1998

29. Summary of workshop findings for antibodies reacting with porcine T-cells and activation antigens:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Sver, L., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W., Barbosa, I. R., Zuckermann, F. A., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Sver, L., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W., Barbosa, I. R., Zuckermann, F. A., and Saalmüller, A.

Published
1998

30. Report on the analyses of mAb reactive with porcine CD8 for the 2. International Swine CD Workshop

Author

Zuckermann, F. A., Pescovitz, M. D., Aasted, B., Dominguez, J., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W. C., Barbosa, I. R., Saalmüller, A., Zuckermann, F. A., Pescovitz, M. D., Aasted, B., Dominguez, J., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W. C., Barbosa, I. R., and Saalmüller, A.

Published
1998

31. Immunoprecipitation studies of monoclonal antibodies submitted to the 2. International Swine CD Workshop

Author

Aasted, B., Gori, K., Dominguez, J., Ezquerra, A., Bullido, R., Arn, S., Bianchi, A., Binns, R. M., Chu, R. M., Davis, W. C., Denham, S., Haverson, K., Jensen, K. T., Kim, Y. B., Magyar, A., Petersen, K. R., Saalmüller, A., Sachs, D. H., Schütt, C., Shimizu, M., Stokes, C. R., Whitfall, T., Yang, H., Zuckermann, F. A., Aasted, B., Gori, K., Dominguez, J., Ezquerra, A., Bullido, R., Arn, S., Bianchi, A., Binns, R. M., Chu, R. M., Davis, W. C., Denham, S., Haverson, K., Jensen, K. T., Kim, Y. B., Magyar, A., Petersen, K. R., Saalmüller, A., Sachs, D. H., Schütt, C., Shimizu, M., Stokes, C. R., Whitfall, T., Yang, H., and Zuckermann, F. A.

Published
1998

32. Analysis of the immunological cross reactivities of 213 well characterized monoclonal antibodies with specificities against various leucocyte surface antigens of human and 11 animal species

Author

Brodersen, R., Bijlsma, F., Gori, K., Jensen, K. T., Chen, W., Dominguez, J., Haverson, K., Moore, P. F., Saalmüller, A., Sachs, D. H., Slierendrecht, W. J., Stokes, C. R., Vainio, O., Zuckermann, F. A., Aasted, B., Brodersen, R., Bijlsma, F., Gori, K., Jensen, K. T., Chen, W., Dominguez, J., Haverson, K., Moore, P. F., Saalmüller, A., Sachs, D. H., Slierendrecht, W. J., Stokes, C. R., Vainio, O., Zuckermann, F. A., and Aasted, B.

Published
1998

33. Analyses of monoclonal antibodies reacting with porcine CD3:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Lackovic, G., Kirkham, P., Parkhouse, R. M. E., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Lackovic, G., Kirkham, P., Parkhouse, R. M. E., and Saalmüller, A.

Published
1998

34. Analyses of monoclonal antibodies reacting with porcine CD5:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Tomaskovic, M., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Saalmüller, A., Aasted, B., Pescovitz, M. D., Book, B. K., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Tomaskovic, M., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Saalmüller, A., and Aasted, B.

Published
1998

35. Immunoprecipitation studies of monoclonal antibodies submitted to the 2. International Swine CD Workshop

Author

Aasted, B., Gori, K., Dominguez, J., Ezquerra, A., Bullido, R., Arn, S., Bianchi, A., Binns, R. M., Chu, R. M., Davis, W. C., Denham, S., Haverson, K., Jensen, K. T., Kim, Y. B., Magyar, A., Petersen, K. R., Saalmüller, A., Sachs, D. H., Schütt, C., Shimizu, M., Stokes, C. R., Whitfall, T., Yang, H., Zuckermann, F. A., Aasted, B., Gori, K., Dominguez, J., Ezquerra, A., Bullido, R., Arn, S., Bianchi, A., Binns, R. M., Chu, R. M., Davis, W. C., Denham, S., Haverson, K., Jensen, K. T., Kim, Y. B., Magyar, A., Petersen, K. R., Saalmüller, A., Sachs, D. H., Schütt, C., Shimizu, M., Stokes, C. R., Whitfall, T., Yang, H., and Zuckermann, F. A.

Published
1998

36. Report on the analyses of mAb reactive with porcine CD8 for the 2. International Swine CD Workshop

Author

Zuckermann, F. A., Pescovitz, M. D., Aasted, B., Dominguez, J., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W. C., Barbosa, I. R., Saalmüller, A., Zuckermann, F. A., Pescovitz, M. D., Aasted, B., Dominguez, J., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W. C., Barbosa, I. R., and Saalmüller, A.

Published
1998

37. Analyses of monoclonal antibodies reacting with porcine wCD6:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Petrinec, N., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Bullido, R., Trebichavsky, I., Novikov, B., Valpotic, I., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Petrinec, N., and Saalmüller, A.

Published
1998

38. Summary of workshop findings for antibodies reacting with porcine T-cells and activation antigens:results from the 2. International Swine CD Workshop

Author

Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Sver, L., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W., Barbosa, I. R., Zuckermann, F. A., Saalmüller, A., Pescovitz, M. D., Book, B. K., Aasted, B., Dominguez, J., Ezquerra, A., Trebichavsky, I., Novikov, B., Valpotic, I., Sver, L., Nielsen, J., Arn, S., Sachs, D. H., Lunney, J. K., Boyd, P. C., Walker, J., Lee, R., Davis, W., Barbosa, I. R., Zuckermann, F. A., and Saalmüller, A.

Published
1998

39. Overview of the Second International Workshop to define swine cluster of differentiation (CD) antigens

Author

Saalmüller, A., Pauly, T., Lunney, J. K., Boyd, P. C., Aasted, B., Sachs, D. H., Arn, S., Bianchi, A., Binns, R. M., Licence, S., Whyte, A., Blecha, A., Chen, Z., Chu, R. M., Davis, W. C., Denham, S., Yang, H., Whittall, T., Parkhouse, R. M. E., Dominguez, J., Ezquerra, A., Alonso, F., Horstick, G., Howard, C., Sopp, P., Kim, Y. B., Lipp, J., Mackay, C., Magyar, A., McCullough, K., Arriens, A., Summerfield, A., Murtaugh, M., Nielsen, J., Novikov, B., Pescovitz, M. D., Schuberth, H. J., Leibold, W., Schütt, C., Saalmüller, A., Pauly, T., Lunney, J. K., Boyd, P. C., Aasted, B., Sachs, D. H., Arn, S., Bianchi, A., Binns, R. M., Licence, S., Whyte, A., Blecha, A., Chen, Z., Chu, R. M., Davis, W. C., Denham, S., Yang, H., Whittall, T., Parkhouse, R. M. E., Dominguez, J., Ezquerra, A., Alonso, F., Horstick, G., Howard, C., Sopp, P., Kim, Y. B., Lipp, J., Mackay, C., Magyar, A., McCullough, K., Arriens, A., Summerfield, A., Murtaugh, M., Nielsen, J., Novikov, B., Pescovitz, M. D., Schuberth, H. J., Leibold, W., and Schütt, C.

Published
1998

40. Summary of the first round analyses of the 2. International Swine CD Workshop

Author

Saalmüller, A., Pauly, T., Aasted, B., Jensen, K. T., Sachs, D. H., Nielsen, J., Arn, S., Davis, W. C., Park, Y. H., McCullough, K., Summerfield, A., Murtaugh, M., Pampusch, M. S., Burger, K. D., Laber, J., Pescovitz, M. D., Stokes, C. R., Haverson, K., Boyd, P. C., Lunney, J. K., Saalmüller, A., Pauly, T., Aasted, B., Jensen, K. T., Sachs, D. H., Nielsen, J., Arn, S., Davis, W. C., Park, Y. H., McCullough, K., Summerfield, A., Murtaugh, M., Pampusch, M. S., Burger, K. D., Laber, J., Pescovitz, M. D., Stokes, C. R., Haverson, K., Boyd, P. C., and Lunney, J. K.

Published
1998

41. Expression of an allogeneic MHC DRB transgene, through retroviral transduction of bone marrow, induces specific reduction of alloreactivity.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Emery, D W, Sablinski, T, Shimada, H, Germana, S, Gianello, Pierre, Foley, A, Shulman, S, Arn, S, Fishman, J, Lorf, T, Nickeleit, V, Colvin, R B, Sachs, D H, LeGuern, C, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Emery, D W, Sablinski, T, Shimada, H, Germana, S, Gianello, Pierre, Foley, A, Shulman, S, Arn, S, Fishman, J, Lorf, T, Nickeleit, V, Colvin, R B, Sachs, D H, and LeGuern, C

Abstract

BACKGROUND: Transfer of MHC class II genes, through allogeneic bone marrow (BM) transplantation, induced long-lasting acceptance of renal allografts in miniature swine. To adapt this approach to the clinic, we have now examined whether somatic transfer of allogeneic class II DR genes, into otherwise autologous bone marrow cells (BMC), can provide the matching required for inducing immune tolerance. METHODS: Autologous BMC were transduced ex vivo with recombinant retroviruses for allogeneic DRB followed by BM transplantation. The recipients were then challenged with kidney allografts solely matched to the DRB transgene. RESULTS: Five miniature swine received autologous BMC conditioned with growth factors and transduced with recombinant retrovirus vectors containing allogeneic (n=4) or syngeneic (n=1) class II DRB genes and a drug-resistance marker. Expression of retrovirus-derived products in BM-derived cells was demonstrated by the detection of drug-resistant colony-forming progenitors and the presence of DRB retrovirus transcripts in peripheral cells. Analysis of selective mixed lymphocyte reaction responses to DR or DQ antigens indicated decreased reactivity toward the transduced DR gene product. Among all of the animals receiving fully mismatched kidney allografts, but with DRB matched to the transduced DRB, the one with the highest gene transduction rate showed stable allograft function and essentially normal renal histology for 2.5 years. A control animal, which received a syngeneic DRB gene, rejected its kidney allograft in 120 days after an earlier rejection crisis. CONCLUSIONS: These studies demonstrate that allogeneic MHC gene transfer into BM provides a new strategy for inducing tolerance across MHC barriers.

Published
1997

42. Influence of the thymus on transplantation tolerance in miniature swine.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Yamada, K, Gianello, Pierre, Ierino, F L, Shimizu, A, Meehan, S, Colvin, R B, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Yamada, K, Gianello, Pierre, Ierino, F L, Shimizu, A, Meehan, S, Colvin, R B, and Sachs, D H

Abstract

TOLERANCE to kidney allografts in miniature swine is uniformly induced by a 12-day course of cyclosporine A (CyA) across a two-haplotype class I disparity. Second kidney allografts, SLA-matched to the first donor, are accepted without additional immunosuppression, suggesting a systemic mechanism of tolerance. We studied the role of the thymus in tolerance to renal allografts in this model.

Published
1997

43. Role of the thymus in transplantation tolerance in miniature swine. I. Requirement of the thymus for rapid and stable induction of tolerance to class I-mismatched renal allografts.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Yamada, K, Gianello, Pierre, Ierino, F L, Lorf, T, Shimizu, A, Meehan, S, Colvin, R B, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Yamada, K, Gianello, Pierre, Ierino, F L, Lorf, T, Shimizu, A, Meehan, S, Colvin, R B, and Sachs, D H

Abstract

The almost uniform failure in transplant patients of tolerance-inducing regimens that have been found to be effective in rodents, has made it necessary to examine large animal models before testing of new approaches clinically. Miniature swine have been shown to share many relevant immunologic parameters with humans, and because of their reproducible genetics, have proved extremely useful in providing such a large animal model. We have previously shown that indefinite systemic tolerance to renal allografts in miniature swine is induced in 100% of cases across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-d course of Cyclosporine A (CyA), in contrast to irreversible rejection observed uniformly without CyA treatment. In the present study, we have examined the role of the thymus during the induction of tolerance by performing a complete thymectomy 21 d before renal transplantation. This analysis demonstrated a striking difference between thymectomized and nonthymectomized animals. Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25(+)) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti-donor CTL reactivity in vitro. Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25(+) cells and no anti-donor CTL response in vitro. These results indicate that the thymus is required for rapid and stable induction of tolerance.

Published
1997

44. Pig to monkey bone marrow and kidney xenotransplantation.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Sablinski, T, Gianello, Pierre, Bailin, M, Bergen, K S, Emery, D W, Fishman, J A, Foley, A, Hatch, T, Hawley, R J, Kozlowski, T, Lorf, T, Meehan, S, Monroy, R, Powelson, J A, Colvin, R B, Cosimi, A B, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Sablinski, T, Gianello, Pierre, Bailin, M, Bergen, K S, Emery, D W, Fishman, J A, Foley, A, Hatch, T, Hawley, R J, Kozlowski, T, Lorf, T, Meehan, S, Monroy, R, Powelson, J A, Colvin, R B, Cosimi, A B, and Sachs, D H

Abstract

The intensity of discordant xenograft cellular rejection makes it unlikely that safe doses of immunosuppressive drugs will alone be sufficient to permit long-term survival. We have therefore concentrated our efforts on establishing tolerance to xenogeneic organs through lymphohematopoietic chimerism and the elimination of preformed natural antibodies (nAbs).

Published
1997

45. Long-term acceptance of primarily vascularized renal allografts in miniature swine. Systemic tolerance versus graft adaptation.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Gianello, Pierre, Yamada, K, Fishbein, J M, Lorf, T, Nickeleit, V, Colvin, R B, Arn, J S, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Gianello, Pierre, Yamada, K, Fishbein, J M, Lorf, T, Nickeleit, V, Colvin, R B, Arn, J S, and Sachs, D H

Abstract

We have previously demonstrated that tolerance to two-haplotype class I-mismatched renal allografts can be induced uniformly by a short course of cyclosporine. We report here that following transplant nephrectomy, 8 such long-term acceptor animals all accepted a second renal transplant MHC matched to the original donor without additional immunosuppression. These results indicate that the mechanism of tolerance to primarily vascularized renal allografts involves modification of the host's immune system by the first transplant. To assess the possibility that "graft adaptation" is also involved in the maintenance of tolerance, we retransplanted class I-disparate kidneys from tolerant animals into naive recipients MHC matched to the original recipient. Three of 4 such transplants were rejected acutely, while one animal demonstrated a markedly prolonged survival, but also eventually rejected. These results, therefore, demonstrate that: (1) graft adaptation is not required in order to maintain tolerance; (2) graft acceptance involves induction of systemic tolerance; and (3) graft adaptation may participate in kidney graft prolongation but is not sufficient to transfer tolerance to a secondary host.

Published
1996

46. Effect of major histocompatibility complex matching on the development of tolerance to primarily vascularized renal allografts: a study in miniature swine.

Author

Harvard Medical School - Transplantation biology research center, MGH, Boston, Gianello, Pierre, Sachs, D H, Harvard Medical School - Transplantation biology research center, MGH, Boston, Gianello, Pierre, and Sachs, D H

Abstract

Prevention of rejection and the induction of transplantation tolerance are two related but separable phenomena that must both be considered in the analysis of the response to a transplanted organ. It is frequently hard to separate these phenomena in assessing the outcome of clinical transplants, because patients are rarely studied in the absence of immunosuppressive agents. Use of our partially inbred miniature swine has permitted us to examine the effects of selective MHC matching on transplant survival, and the data indicate that matching has an effect on both phenomena. Prevention of early rejection with CyA was possible for all mismatches examined, although it was clearly more difficult with increasing degrees of mismatching. On the other hand, tolerance induction after cessation of the immunosuppressive agent was dependent on presence of at least one matched MHC locus between the donor and recipient, with complete class II matching appearing to be the most successful way of assuring long-term graft survival. It is also apparent from our data that although durable tolerance to primarily vascularized renal allografts could be induced across a variety of selective MHC disparities, all cases involving a class II mismatch (ie, selective class I matched or one-haplotype full MHC mismatched kidney allografts) underwent spontaneously reversible rejection crises during the early follow-up period. Such a clinical course might be unacceptable for human clinical trials, even though the transient renal dysfunction may reflect events involved in tolerance induction rather than true rejection (Gianello et al: Immunol Rev 133:19, 1993.). Indeed, we do not yet know whether or not further immunosuppressive treatment at the times of such crises may prevent rather than facilitate the induction of tolerance. On the other hand, in the case of selective two-haplotype class I mismatch the regimen utilized was capable of inducing tolerance to renal allografts in 100% of the recipients

Published
1996

47. Molecular identification of porcine interleukin 10: regulation of expression in a kidney allograft model.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Blancho, G, Gianello, Pierre, Germana, S, Baetscher, M, Sachs, D H, LeGuern, C, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Blancho, G, Gianello, Pierre, Germana, S, Baetscher, M, Sachs, D H, and LeGuern, C

Abstract

Clones encoding porcine interleukin 10 (IL-10) were isolated from a cDNA library produced from phytohemagglutinin-activated pig peripheral blood mononuclear cells. The porcine IL-10 nucleotide sequence was found to be highly homologous to the rat, mouse, and human IL-10 counterparts and to one of the open reading frames from the Epstein-Barr virus. In addition, pig IL-10 caused inhibition of gamma-interferon gene transcription as determined by a bioassay. To investigate the possible immunomodulatory role of IL-10, its expression during the induction of tolerance to kidney allografts by cyclosporin A in miniature swine was also investigated. Delayed expression and higher levels of IL-10 were observed in tolerant animals compared with animals rejecting their allografts. Since tolerance is achieved by a short course of cyclosporin A, we have also studied the in vitro effect of this drug on IL-10 gene transcription in blood mononuclear cells and have found that cyclosporin A inhibits IL-10 gene activation in T cells but does not interfere with IL-10 transcription in lipopolysaccharide-activated cells. These results suggest that the overexpression of IL-10, observed in cell populations infiltrating grafts from tolerant animals, may be a function of monocytes and/or B cells.

Published
1995

48. Humoral response of miniature swine tolerant to class I mismatched renal allografts.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Giangrande, I, Gianello, Pierre, Lorf, T, Vitiello, D, LeGuern, C, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Giangrande, I, Gianello, Pierre, Lorf, T, Vitiello, D, LeGuern, C, and Sachs, D H

Published
1995

49. Induction of tolerance to renal allografts across single-haplotype MHC disparities in miniature swine.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Gianello, Pierre, Lorf, T, Yamada, K, Fishbein, J M, Nickeleit, V, Vitiello, D M, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Gianello, Pierre, Lorf, T, Yamada, K, Fishbein, J M, Nickeleit, V, Vitiello, D M, and Sachs, D H

Abstract

We have previously demonstrated that a 12-day course of cyclosporine A (CsA) leads to the induction of tolerance to renal allografts in 100% of recipients selectively mismatched at class I for both haplotypes, and in 71% of recipients selectively mismatched at class II for both haplotypes, but in 0% of recipients mismatched for two haplotypes at both class I and class II. We have postulated that the mechanism by which tolerance is induced may therefore require matching for either class I or class II antigens. One might predict from this hypothesis that tolerance would also be induced in donor-recipient combinations sharing one full haplotype (e.g., AC-->AD), which mimics the clinically relevant transplant combination of parent to offspring. We have therefore investigated the effects of the CsA regimen on renal transplants in this combination. Without immunosuppression, such kidney allografts were uniformly rejected (n = 12; 10.6 +/- 2.4 days). In contrast, a course of CsA (10-13 mg/kg/day) during the first 12 postoperative days induced long-term acceptance of the allograft in 67% (4/6) of recipients. Some acceptor animals also showed specific unresponsiveness to donor antigens as measured by in vitro assays and by failure to develop anti-donor antibodies. Tolerance was confirmed in four of these animals by failure to reject a second transplant SLA-matched to the first kidney donor without additional immunosuppression. These results suggest the feasibility of inducing specific tolerance across a single-haplotype mismatch in the majority of the cases, which could have clinical implications for living-related transplants.

Published
1995

50. Tolerance to class I-disparate renal allografts in miniature swine. Maintenance of tolerance despite induction of specific antidonor CTL responses.

Author

Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Gianello, Pierre, Fishbein, J M, Rosengard, B R, Lorf, T, Vitiello, D M, Arn, J S, Sachs, D H, Harvard Medical School - Transplantation Biology Research Center, MGH, Boston, Gianello, Pierre, Fishbein, J M, Rosengard, B R, Lorf, T, Vitiello, D M, Arn, J S, and Sachs, D H

Abstract

Miniature swine that become tolerant to renal allografts across an MHC class I barrier following a short course of cyclosporine are unresponsive to donor class I antigens in cell-mediated lymphocytotoxicity. However, skin grafts bearing donor class I plus third-party class II antigens are promptly rejected, and the animals then develop marked cell-mediated lymphocytoxic reactivity to donor class I antigens in vitro, but do not reject the kidney transplants. We show here that CTL generation is directed toward the same donor class I antigens as are expressed by the kidney donor, and is not the result of recognition in vitro of the tolerated class I antigen plus peptides of minor antigens shared between the skin graft donor and the stimulator/target cells. We also show that detection by CTLs of peptides expressed by skin but not by kidney is also not a sufficient explantation of the results, since the survival of skin grafts from the kidney donor is also prolonged, even after precursor CTL can be detected in vitro. The data are most consistent with suppression in vivo in tolerant animals of the helper pathways necessary for activation of precursor CTLs. Differences in patterns of cytokine expression by graft infiltrating cells may provide a mechanism for local suppression of help in this model. Finally, we have examined antibody production after sensitizing by skin grafts in long-term tolerant animals and have found that anti-donor class I antibodies are not produced, even though the same animals produce both anti-class II and anti-third-party class I antibodies.

Published
1995

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