Cell-depleted Allogeneic Bone Marrow Transplantation

One of the major obstacles in allogeneic bone marrow transplantation (allo-BMT) is prolonged T cell dysfunction resulting in a variety of infectious complications in the months to years after hematologic engraftment. We previously showed that immobilized extracellular matrix (ECM) proteins such as fibronectin (FN), the CS-1 domain of FN, or collagen (CO) acted synergistically with immobilized antiCD3 to induce T cell proliferation. In addition, the comitogenic effect of ECMs could be mimicked by immobilized mAb reactive with a common f1 chain (CD29) of very late activating (VLA) antigens which include ECM receptors. Since the interaction of T cells with ECMs appears to play an important role in the process of T cell reconstitution following allo-BMT, we examined the expression of VLA antigens (al-a6, fl1) and their functional roles in CD3mediated T cell proliferation at various times after T cell depleted allo-BMT. VLA fl1 as well as VLAcr4, a5, and a6 expression was lower than normal controls during the first 3 mo after allo-BMT and auto-BMT, whereas these expressions returned to normal levels by 4 mo after allo-BMT and auto-BMT. Although cal and a2 were not expressed on lymphocytes from normal controls, these antigens were expressed on lymphocytes at the detectable levels (5-15%) from patients after allo-BMT and auto-BMT. Both CD29 and CD3 were expressed at normal levels on lymphocytes from patients >3 mo after allo-BMT, whereas T cell interaction with ECM through VLA proteins or crosslinking of VLAfl1 expressed by T cells with anti-CD29 mAb results in poor induction of CD3-mediated T cell proliferation for a prolonged period (>1 yr) after allo-BMT. In contrast, T cell proliferation induced by crosslinking of anti-CD2 or anti-CD26 with anti-CD3 was almost fully recovered by 1 yr post-allo-BMT. After autologous BMT, impaired VLAmediated T cell proliferation via the CD3 pathway after auto-BMT returned to normal levels within 1 yr despite no significant difference in CD3 and CD29 expression following either alloor auto-BMT. The adhesion of T cells from postAddress correspondence to Chikao Morimoto, M.D., Division of Tumor Immunology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Receivedfor publication 8 September 1993 and in revised form 18 March 1994. allo-BMT patients to FN-coated plate was normal or increased compared to that of normal controls. Moreover, the induction of the tyrosine phosphorylation of pplO5 protein by the ligation of VLA molecules was not impaired in alloBMT patients. These results suggest that there are some other defects in the process of VLA-mediated signal transduction in such patients. Our results imply that disturbance ofVLA function could explain, at least in part, the persistent immunoincompetent state after allo-BMT and may be involved in susceptibility to opportunistic infections after alloBMT. (J. Clin. Invest. 1994. 94:481-488.)