Abstract
The high rate of persistent hyperglycemia, termed primary nonfunction, after islet allotransplantation in C57BL/6 mice recipients of B10.BR strain islets, as compared with B10.BR recipients of C57BL/6 islets, led to a series of experiments to determine whether islet allograft primary nonfunction was attributable to technical aspects of the transplant procedure or whether it was a consequence of alloimmunity. Primary nonfunction was prevented by systemic pharmacologic immunosuppression of the host with cyclosporine. Selective immunodepletion of host CD4+ and CD8+ T lymphocytes significantly extended the time of classic rejection but did not significantly affect the rate of primary nonfunction. However, modulation of macrophages by administration to the host of silica completely abolished primary nonfunction. These observations, in conjunction with the immunohistological findings of intense macrophage infiltration in islet allografts from recipients exhibiting persistent post-transplant hyperglycemia, support the hypothesis that primary nonfunction results from a cell-mediated host-immune response of rapid onset that is dependent on macrophages or macrophage byproducts as the main effectors.
Full Text
The Full Text of this article is available as a PDF (1.3 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Appels B., Burkart V., Kantwerk-Funke G., Funda J., Kolb-Bachofen V., Kolb H. Spontaneous cytotoxicity of macrophages against pancreatic islet cells. J Immunol. 1989 Jun 1;142(11):3803–3808. [PubMed] [Google Scholar]
- Barker C. F., Frangipane L. G., Silvers W. K. Islet transplantation in genetically determined diabetes. Ann Surg. 1977 Oct;186(4):401–410. doi: 10.1097/00000658-197710000-00001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bunjes D., Hardt C., Röllinghoff M., Wagner H. Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol. 1981 Aug;11(8):657–661. doi: 10.1002/eji.1830110812. [DOI] [PubMed] [Google Scholar]
- Clark E. A., Terasaki P. I., Opelz G., Mickey M. R. Cadaver-kidney transplant failures at one month. N Engl J Med. 1974 Nov 21;291(21):1099–1102. doi: 10.1056/NEJM197411212912102. [DOI] [PubMed] [Google Scholar]
- Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
- Espevik T., Figari I. S., Shalaby M. R., Lackides G. A., Lewis G. D., Shepard H. M., Palladino M. A., Jr Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J Exp Med. 1987 Aug 1;166(2):571–576. doi: 10.1084/jem.166.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gotoh M., Maki T., Satomi S., Porter J., Monaco A. P. Immunological characteristics of purified pancreatic islet grafts. Transplantation. 1986 Oct;42(4):387–390. doi: 10.1097/00007890-198610000-00011. [DOI] [PubMed] [Google Scholar]
- Gray D. W., Sutton R., McShane P., Peters M., Morris P. J. Exocrine contamination impairs implantation of pancreatic islets transplanted beneath the kidney capsule. J Surg Res. 1988 Nov;45(5):432–442. doi: 10.1016/0022-4804(88)90193-x. [DOI] [PubMed] [Google Scholar]
- Kaufman D. B., Rabe F., Platt J. L., Stock P. G., Sutherland D. E. On the variability of outcome after islet allotransplantation. Transplantation. 1988 Jun;45(6):1151–1153. doi: 10.1097/00007890-198806000-00035. [DOI] [PubMed] [Google Scholar]
- Kissmeyer-Nielsen F., Olsen S., Petersen V. P., Fjeldborg O. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet. 1966 Sep 24;2(7465):662–665. doi: 10.1016/s0140-6736(66)92829-7. [DOI] [PubMed] [Google Scholar]
- Mandrup-Poulsen T., Bendtzen K., Nielsen J. H., Bendixen G., Nerup J. Cytokines cause functional and structural damage to isolated islets of Langerhans. Allergy. 1985 Aug;40(6):424–429. doi: 10.1111/j.1398-9995.1985.tb02681.x. [DOI] [PubMed] [Google Scholar]
- McDaniel M. L., Hughes J. H., Wolf B. A., Easom R. A., Turk J. W. Descriptive and mechanistic considerations of interleukin 1 and insulin secretion. Diabetes. 1988 Oct;37(10):1311–1315. doi: 10.2337/diab.37.10.1311. [DOI] [PubMed] [Google Scholar]
- Morrow C. E., Sutherland D. E., Steffes M. W., Kaufman D., Najarian J. S., Bach F. H. Differences in susceptibility to rejection of mouse pancreatic islet allografts disparate for class I or class II major histocompatibility antigens. J Surg Res. 1983 Apr;34(4):358–366. doi: 10.1016/0022-4804(83)90083-5. [DOI] [PubMed] [Google Scholar]
- Morrow C. E., Sutherland D. E., Steffes M. W., Najarian J. S., Bach F. H. H-2 antigen class: effect on mouse islet allograft rejection. Science. 1983 Mar 18;219(4590):1337–1339. doi: 10.1126/science.6402817. [DOI] [PubMed] [Google Scholar]
- Munn S. R., Kaufman D. B., Meloche R. M., Field M. J., Sutherland D. E. Weight-corrected islet counts are predictive of outcome in the canine intrahepatic islet autograft model. Diabetes Res. 1988 Nov;9(3):121–124. [PubMed] [Google Scholar]
- Murphy W. J., Kumar V., Bennett M. Acute rejection of murine bone marrow allografts by natural killer cells and T cells. Differences in kinetics and target antigens recognized. J Exp Med. 1987 Nov 1;166(5):1499–1509. doi: 10.1084/jem.166.5.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murphy W. J., Kumar V., Bennett M. Rejection of bone marrow allografts by mice with severe combined immune deficiency (SCID). Evidence that natural killer cells can mediate the specificity of marrow graft rejection. J Exp Med. 1987 Apr 1;165(4):1212–1217. doi: 10.1084/jem.165.4.1212. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Najarian J. S., Sutherland D. E., Baumgartner D., Burke B., Rynasiewicz J. J., Matas A. J., Goetz F. C. Total or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis. Ann Surg. 1980;192(4):526–542. doi: 10.1097/00000658-198010000-00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nerstrom B., Ladefoged J., Lund F. Vascular complications in 155 consecutive kidney transplantations. Scand J Urol Nephrol. 1972;6(Suppl):65–74. doi: 10.3109/00365597209133647. [DOI] [PubMed] [Google Scholar]
- Platt J. L., Michael A. F. Retardation of fading and enhancement of intensity of immunofluorescence by p-phenylenediamine. J Histochem Cytochem. 1983 Jun;31(6):840–842. doi: 10.1177/31.6.6341464. [DOI] [PubMed] [Google Scholar]
- Pukel C., Baquerizo H., Rabinovitch A. Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin, and interleukin 1. Diabetes. 1988 Jan;37(1):133–136. doi: 10.2337/diab.37.1.133. [DOI] [PubMed] [Google Scholar]
- Sandler S., Andersson A., Hellerström C. Inhibitory effects of interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets. Endocrinology. 1987 Oct;121(4):1424–1431. doi: 10.1210/endo-121-4-1424. [DOI] [PubMed] [Google Scholar]
- Sarmiento M., Dialynas D. P., Lancki D. W., Wall K. A., Lorber M. I., Loken M. R., Fitch F. W. Cloned T lymphocytes and monoclonal antibodies as probes for cell surface molecules active in T cell-mediated cytolysis. Immunol Rev. 1982;68:135–169. doi: 10.1111/j.1600-065x.1982.tb01063.x. [DOI] [PubMed] [Google Scholar]
- Scharp D., Lacy P., Ricordi C., Boyle P., Santiago J., Cryer P., Gingerick R., Jaffe A., Anderson C., Flye W. Human islet transplantation in patients with type I diabetes. Transplant Proc. 1989 Feb;21(1 Pt 3):2744–2745. [PubMed] [Google Scholar]
- Schwizer R. W., Leiter E. H., Evans R. Macrophage-mediated cytotoxicity against cultured pancreatic islet cells. Transplantation. 1984 Jun;37(6):539–544. doi: 10.1097/00007890-198406000-00002. [DOI] [PubMed] [Google Scholar]
- Seemayer T. A., Tannenbaum G. S., Goldman H., Colle E. Dynamic time course studies of the spontaneously diabetic BB Wistar rat. III. Light-microscopic and ultrastructural observations of pancreatic islets of Langerhans. Am J Pathol. 1982 Feb;106(2):237–249. [PMC free article] [PubMed] [Google Scholar]
- Sutherland D. E., Matas A. J., Najarian J. S. Pancreatic islet cell transplantation. Surg Clin North Am. 1978 Apr;58(2):365–382. doi: 10.1016/s0039-6109(16)41489-1. [DOI] [PubMed] [Google Scholar]
- Sutherland D. Pancreas and islet transplant registry data. World J Surg. 1984 Apr;8(2):270–275. doi: 10.1007/BF01655147. [DOI] [PubMed] [Google Scholar]
- Van Loveren H., Snoek M., Den Otter W. Effects of silica on macrophages and lymphocytes. J Reticuloendothel Soc. 1977 Dec;22(6):523–531. [PubMed] [Google Scholar]
- Walker R., Bone A. J., Cooke A., Baird J. D. Distinct macrophage subpopulations in pancreas of prediabetic BB/E rats. Possible role for macrophages in pathogenesis of IDDM. Diabetes. 1988 Sep;37(9):1301–1304. doi: 10.2337/diab.37.9.1301. [DOI] [PubMed] [Google Scholar]
- Warner J. F., Dennert G. Bone marrow graft rejection as a function of antibody-directed natural killer cells. J Exp Med. 1985 Mar 1;161(3):563–576. doi: 10.1084/jem.161.3.563. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Warnock G. L., Rajotte R. V. Critical mass of purified islets that induce normoglycemia after implantation into dogs. Diabetes. 1988 Apr;37(4):467–470. doi: 10.2337/diab.37.4.467. [DOI] [PubMed] [Google Scholar]
- White R. I., Jr, Najarian J., Loken M., Amplatz K. Arteriovenous complications associated with renal transplantation. Radiology. 1972 Jan;102(1):29–36. doi: 10.1148/102.1.29. [DOI] [PubMed] [Google Scholar]
- Williams G. M., Hume D. M., Hudson R. P., Jr, Morris P. J., Kano K., Milgrom F. "Hyperacute" renal-homograft rejection in man. N Engl J Med. 1968 Sep 19;279(12):611–618. doi: 10.1056/NEJM196809192791201. [DOI] [PubMed] [Google Scholar]
