Partial review of immunotherapeutic pharmacology in stem cell transplantation

Philip Jay Bierman, Fuminori Abe, Suleyman Buyukberber, Kazuhiko Ino, James E Talmadge

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

In two separate lymphoma populations, we examined immune reconstitution following high dose chemotherapy (HDT) and bone marrow transplantation (BMT). In the first study we followed immune reconstitution for one year after HDT and BMT. In the second study we examined the ability of the orally active immunomodulator, Bestatin to augment immune reconstitution following HDT and BMT. The studies on immune reconstitution following HDT and BMT were undertaken in a cohort of non-Hodgkin's lymphoma (NHL) patients (n=35) and examined the peripheral blood (PS) leukocyte subsets and their in vitro functions. Our results demonstrate that monocyte and natural killer (NK) cell engraftment occurred more rapidly then did T cell reconstitution. We also observed a significant decrease in the CD4:CD8 ratio post- transplantation as compared to normal PB donors due to a decrease in CD4+ cells. In addition, following HDT and BMT, measures of T cell function (phytohemagglutinin [PHA] mitogenesis) and T helper cell activity (pokeweed mitogen [PWM] mitogenesis) were consistently depressed as compared to cells from normal PB. Further, we demonstrate a correlation between the loss of T cell function and the frequency of circulating monocytes, suggesting a cause-effect relationship. Despite the dysfunction in T cells following HDT and BMT, immune-modulating agents can still augment the immune function. One such drug is Bestatin (ubenimex), an inhibitor of aminopeptidase (AP) that binds to CD13 on macrophage/monocytes. To examine its immune modulatory activity after HDT and BMT, a dose finding (10, 30, 90 and 180 mg/day) phase Ib trial was conducted with 30 Hodgkin's disease (HD) and NHL patients who received no drug (control), or Bestatin daily for 60 days following BMT. In these studies, Bestatin administration was initiated when the absolute neutrophil count was greater than 250/mm3 on two consecutive days. These studies revealed that Bestatin significantly increased the PHA and PWM responses in a dose-dependent manner. Flow cytometric analysis revealed a significant increase in NK cells (CD56+), B cells (CD19+), as well as the CD4:CD8 cell ratio. The latter observation was associated largely with a depression in the percent of CD8+ T cells as opposed to an increase in CD4+ T cells. We conclude that despite the peripheral tolerance observed following HDT and BMT, Bestatin could significantly increase some, but not all, immune surrogates.

Original languageEnglish (US)
Pages (from-to)221-236
Number of pages16
JournalIn Vivo
Volume14
Issue number1
StatePublished - Jan 1 2000

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Stem Cell Transplantation
Chemotherapy
Stem cells
Bone Marrow Transplantation
Bone
T-cells
Pharmacology
Drug Therapy
T-Lymphocytes
Monocytes
Pokeweed Mitogens
CD4-CD8 Ratio
Phytohemagglutinins
Natural Killer Cells
Non-Hodgkin's Lymphoma
Peripheral Tolerance
Aminopeptidases
Macrophages
Drug and Narcotic Control
Immunologic Factors

Keywords

  • BMT
  • Bestatin
  • HDT
  • Hodgkin's disease
  • Immunomodulator
  • NHL

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology

Cite this

Partial review of immunotherapeutic pharmacology in stem cell transplantation. / Bierman, Philip Jay; Abe, Fuminori; Buyukberber, Suleyman; Ino, Kazuhiko; Talmadge, James E.

In: In Vivo, Vol. 14, No. 1, 01.01.2000, p. 221-236.

Research output: Contribution to journalArticle

Bierman, Philip Jay ; Abe, Fuminori ; Buyukberber, Suleyman ; Ino, Kazuhiko ; Talmadge, James E. / Partial review of immunotherapeutic pharmacology in stem cell transplantation. In: In Vivo. 2000 ; Vol. 14, No. 1. pp. 221-236.
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