B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 307

recipient. These antigens are not derived from germ-line polymorphisms in
the recipient but would be derived from unique mutations in the tumor cell
or abnormal expression of other tumor-associated antigens. Donor T cells
targeting these antigens would be expected to induce GVL without cGVHD
and represent a potential mechanism for separating these two immuno-
logic responses.

One approach to identifying tumor-specific antigens has employed pep-
tide-binding prediction algorithms to identify epitopes from mutated can-
cer proteins that would be presented in the context of a specific MHC. As
proof of principle, identification of one such epitope of the BCR-ABL fusion
gene product allowed for the detection of a tumor-specific T-cell response
against this epitope presented in the context of the appropriate MHC from
the blood of a patient following curative ASCT for CML [111] . Identifica-
tion of such antigens has also been aided by the use of donor lymphocyte
infusion (DLI) for the treatment of disease relapse post-transplantation
[112-116] . DLI following T-cell-depleted transplantation has been shown to
result in more rapid B-cell reconstitution as well as a more rapid improve-
ment in T-cell receptor Vβ repertoire complexity despite no difference in
the kinetics and pattern of T-cell recovery [117] . Some leukemia patients
who respond to DLI have marrow that has been infiltrated by plasma cells,
suggesting a role for humoral immunity. In addition to inducing remissions
among relapsed patients post-transplantation, DLI does result in increased
incidence of GVHD. DLI may be effective, then, in enhancing both humoral
and cellular immunity to both tumor and host mHAs. Patients with CML
who have relapsed after ASCT do not have detectable CD8 T-cell clones or
circulating antibodies that are specific for known CML antigens prior to
receiving DLI. Following DLI, however, these immune responses are evi-
dent in patients who have had a disease response [114] . Analysis of the bone
marrow from such patients before DLI reveals the presence of epitope-spe-
cific CD8 T-cell clones in low numbers, suggesting that DLI is effective in
eliciting the expansion of preexisting cytotoxic T cells and a coordinated
humoral response directed against tumor cells. Comparison of cDNA or
protein microarray screens of serum from transplant patients before and
after DLI has led to the identification of multiple immunogenic antigens
that are expressed in greater numbers in tumor and hematopoietic cells and
elicit quantifiable and specific antibody responses in patients with disease
that has responded to chemotherapy, ASCT, and DLI and against which spe-
cific CD8 clones can be isolated from these same patients. Taken together,
these data point toward a coordinated cellular and humoral immune
response underlying the GVL/GVT effect of ASCT, one that can potentially
be harnessed against the tumor and not against normal recipient tissue if it
is directed against unique tumor antigens.

311

From pathogenesis to therapy: cGVHD and GVL/GVT

The enhanced understanding of the biology behind cGVHD and GVL/GVT
and the appreciation of their differences has led to a number of therapies
and interventions aimed at treating cGVHD, enhancing GVL/GVT, and sep-
arating the two to reduce relapse- and non-relapse-related mortality follow-
ing transplantation ( Tables 14.1-14.3 ).