B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 314

administration of cytokines or cytokine inhibitors to shift the dominant
immune response from a Th2 to a Th1 phenotype, as well as to decrease
the inflammation associated with transplantation and conditioning to
decrease the risk of alloimmune activation in GVHD target organs. Results
of studies in mice with anti-TNF-α and IL-1 antibodies have been mixed,
however, perhaps owing to differential timing of the administration of these
agents following transplant [11,105,158,159] . IL-11 administration has been
investigated based on its ability to abrogate conditioning-related inflam-
mation and thrombocytopenia associated with ASCT [160] . Unfortunately it
resulted in multiorgan toxicity [161] . A better understanding of the kinetics
of immune recovery following transplantation and the temporal pattern of
cytokines that drive and define that recovery is needed to facilitate effective
manipulation of the immune environment for the prevention of GVHD and
enhancement of GVL/GVT. Immune reconstitution is largely regulated by
homeostatic cytokines and this is an area of future research that may lead to
new approaches to enhance and modulate recovery of various donor popu-
lations after transplant.

Conclusions

318

Allogeneic stem cell transplantation is a potentially curative treatment for
many refractory and high-risk hematologic malignancies that would other-
wise be fatal with our best current conventional therapies. Outcomes after
ASCT have improved steadily in the past decade but GVHD, disease relapse,
infection, and risks associated with immune-suppressive therapies con-
tinue to be major obstacles. Understanding the mechanisms of GVHD and
the anti-tumor immunologic potential of ASCT should result in improved
strategies to treat and prevent GVHD while enhancing the anti-tumor effect
of transplantation. While our current understanding of the immunology of
both processes is evolving, what we have learned in the past several decades
has led to new therapeutic advances. The mechanisms of loss of immune
tolerance, the cytokines that direct immune responses, and the impor-
tance of Treg- and B-cell dynamics post-transplantation have resulted in
the investigation of cytokine administration and inhibition to alter immune
responses, B-cell-directed therapies, and T-cell-adoptive therapies and
tumor vaccine approaches, all of which have demonstrated potential in
enhancing the safety and efficacy of stem cell transplantation.

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