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Delayed infusion of immunocompetent donor cells after bone marrow transplantation breaks graft-host tolerance allows for persistent antileukemic reactivity without severe graft-versus-host disease. Blood 1995 Jun 01;85(11):3302-12

Date

06/01/1995

Pubmed ID

7756664

DOI

10.1182/blood.v85.11.3302.bloodjournal85113302

Scopus ID

2-s2.0-0029068065 (requires institutional sign-in at Scopus site)   135 Citations

Abstract

The development of graft-host tolerance after bone marrow transplantation (BMT) is crucial to avoid the problems of graft-versus-host disease (GVHD) and graft rejection. GVHD can be eliminated by depleting mature donor T cells from the BM inoculum, thereby facilitating the development of graft-host tolerance. However, T-cell depletion often results in an increased incidence of graft rejection and an increased frequency of leukemia relapse. Thus, although graft-host tolerance is a desirable outcome, it can pose a significant threat to leukemia-bearing hosts. Using a major histocompatability complex (MHC)-matched allogeneic model of BMT (B10.BR into AKR), we found that irradiated recipients given donor BM alone displayed mixed T-cell chimerism and did not develop GVHD. Graft-host tolerance developed by 8 weeks after BMT in these chimeras, and they were susceptible to low-dose leukemia challenge. When sufficient numbers of donor spleen cells, as a source of T-cells, were added to the BM graft, AKR hosts developed severe and lethal GVHD. Antihost reactive donor T cells persisted in chimeras undergoing GVHD, indicating that graft-host tolerance did not develop. When administration of the spleen cells was delayed for 7 to 21 days after BMT, there was significantly less mortality because of GVHD. Day 21 was the optimal time for infusion of cells without development of GVHD. Graft-host tolerance was broken by the delayed infusion of donor cells, as indicated by the persistence of antihost-reactive donor T cells in these chimeras in T-cell receptor cross-linking and mixed lymphocyte reaction assays. Importantly, the persistence of antihost-reactive donor T cells correlated with along-term antileukemic effect that was still present at 100 days after transplant. Multiple infusions of immunocompetent donor cells could be administered without increasing the risk for GVHD if delayed until 21 days post-BMT. Delayed infusions of donor spleen cells also resulted in a long-term antileukemic effect in the absence of GVHD in an MHC-haplotype-mismatched model of BMT (SJL into [SJL x AKR]F1). Although delayed infusion of normal donor cells did not induce GVHD, spleen cells from donors previously sensitized to host alloantigens induced GVHD when infused 21 days after BMT. Thus, the ability of previously activated cells to induce GVHD was not inhibited in the same manner as naive cells. Results from limiting dilution analysis assays indicated that alloactivated interleukin-2-secreting CD4+ T cells were preferentially inhibited over cytolytic T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Author List

Johnson BD, Truitt RL

Author

Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bone Marrow Transplantation
CD4-Positive T-Lymphocytes
Female
Graft Rejection
Graft vs Host Disease
Histocompatibility
Immune Tolerance
Immunocompetence
Immunotherapy
Leukemia, Experimental
Lymphocyte Activation
Lymphocyte Culture Test, Mixed
Male
Mice
Mice, Inbred AKR
Radiation Chimera
Spleen
T-Lymphocytes
T-Lymphocytes, Cytotoxic
Time Factors