The sporadic first examples of kidney alloengraftment (See: The First Human Bone Marrow & Kidney Transplantations) followed by Dr. Starzl’s series of 1962-63 (See: Drug Immunosuppression) opened the floodgates of organ transplantation and redirected transplant-related research and its funding. Kidney alloengraftment seemingly had no relation to either the donor leukocyte chimerism or the prerequisite of tissue matching epitomized by the mouse tolerance models (See: The Leukocyte Chimerism-Tolerance Association). However, the possibility remained that organ transplant outcomes would correlate with gradations of tissue match. This hypothesis was tested by Dr. Starzl and Dr. Paul Terasaki (UCLA) (Fig. 1). First, they retrospectively determined the matches of still-surviving 1962-3 Colorado kidney recipients and their live donors [ref 1]. Then, they prospectively matched the donor pairs of 1965-70 cases [ref 2]. In both studies, the HLA match had little correlation with the clinical outcomes unless it was perfect. A final report was presented by Starzl to the American Surgical Association in April 1970, and by Terasaki 5 months later to the biennial congress of The Transplantation Society. When the results did not conform to NIH expectations of a step-wise matching effect, funding for the project was rescinded (See: Chapter 11, The Puzzle People). Undeterred, Terasaki generated alternative funding. With ultimate validation of the study conclusions, he moved on to the undisputed leadership in the tissue matching field.
For Starzl, the study findings breathed life into liver (and thoracic organ) transplantation where most candidates could not wait for a well-matched donor. However, the definitive Terasaki-Starzl investigation had surprisingly little effect on policies of kidney transplantation. The resulting disharmony (Fig. 2) was not resolved until Starzl’s 1992 microchimerism discoveries (See: Discovery of Microchimerism, A New Transplant Immunology Paradigm, Generalization of the Transplant Paradigm and Therapeutic Implications) explained the poor discrimination of tissue matching. In between times, the 1984 National Transplant Act was passed. The law included a contract eventually let to the United Network for Organ Sharing (UNOS) to develop an equitable cadaver kidney distribution plan. This charge was met by the verbatim adoption in 1987 of the allocation system already in use in Pittsburgh [ref. 3]. In the contract, organs perfectly matched with candidates in a national pool automatically were directed to those targets while minimal credit was given for lesser degrees of matching. Over the next 2 years, however, modifications by regional UNOS subcommittees discarded essentially all candidacy factors other than linear-scale HLA matching. As predicted by Dr. Starzl at the time, this created a system-wide bias against African Americans. The injustice was not acknowledged or corrected until a decade later.
Starzl’s other contributions to tissue matching were his description of the antibody-mediated rejection that destroys organs within a few minutes or hours after their transplantation (so-called hyperacute rejection) (Fig. 3). He showed that this kind of immediate graft loss could be avoided with his ABO blood group compatibility guidelines (See: Experience in Renal Transplantation, Chapter 6) and by use of the cytotoxic antibody crossmatch described by Terasaki, Marchioro, and Starzl in 1965 [ref 4]. He subsequently elucidated the mechanisms of innate immunity responsible for hyperacute rejection [ref 4].
The citation frequencies of the papers cited in this summary and written over a two-decade period are graphically illustrated in Figure 4. The bimodal distribution of citations related to all papers written by Starzl and fitting into the Theme of Tissue Matching is shown in Figure 5. A heat map demonstrating the relative annual citation frequencies of these publications is seen in Figure 6.
- Starzl TE, Marchioro TL, Terasaki PI, Porter KA, Faris TD, Herrmann TJ, Vredevoe DL, Hutt MP, Ogden DA, Waddell WR: Chronic survival after human renal homotransplantations: Lymphocyte-antigen matching, pathology and influence of thymectomy. Ann Surg 162:749-787, 1965.
- Starzl TE, Porter KA, Andres G, Halgrimson CG, Hurwitz R, Giles G, Terasaki PI, Penn I, Schroter GT, Lilly J, Starkie SJ, Putnam CW: Long-term survival after renal transplantation in humans: With special reference to histocompatibility matching, thymectomy, homograft glomerulonephritis, heterologous ALG, and recipient malignancy. Ann Surg 172:437-472, 1970.
- Starzl TE, Hakala T, Tzakis A, Gordon R, Stieber A, Makowka L, Klimoski J, Bahnson HT: A multifactorial system for equitable selection of cadaveric kidney recipients. JAMA 257:3073-3075, 1987.
- See Tissue Matching Appendix for complete references and rank order citations
Bimodal curve illustrating cumulative citation frequencies of all publications by Dr. Starzl within the Theme of Tissue Matching.