Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge.

The successful elimination of pathogenic cells and microorganisms by the humoral immune system relies on effective interactions between host immunoglobulins and Fc gamma receptors on effector cells, in addition to the complement system. Essential Ig motifs that direct those interactions reside within the conserved IgG lower hinge/CH2 interface. We noted that a group of tumor-related and microbial proteases cleaved human IgG1s in that region, and the "nick" of just one of the heavy chains profoundly inhibited IgG1 effector functions.

Human anti-IgG1 hinge autoantibodies reconstitute the effector functions of proteolytically inactivated IgGs.

A number of proteases of potential importance to human physiology possess the ability to selectively degrade and inactivate Igs. Proteolytic cleavage within and near the hinge domain of human IgG1 yielded products including Fab and F(ab')(2) possessing full Ag binding capability but absent several functions needed for immune destruction of cellular pathogens. In parallel experiments, we showed that the same proteolytically generated Fabs and F(ab')(2)s become self-Ags that were widely recognized by autoantibodies in the human population.

Telomerase vaccination has no detectable effect on SCID-repopulating and colony-forming activities in the bone marrow of cancer patients.

Objectives: The telomerase reverse transcriptase hTERT is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes (CTL). We have previously shown that vaccination of cancer patients against hTERT induces functional anti-tumor CTL in vivo, but it is not known whether hTERT vaccination harms normal cells expressing the enzyme, especially hematopoietic stem cells and progenitors.

Patients And Methods: We employed colony-forming cell (CFC) assays, long-term in vitro cultures, and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulation studies to evaluate the effects of hTERT vaccination on hematopoietic progenitors and stem cells in cancer patients following treatment.

Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia.

Human hematopoietic stem cells (HSCs) are generally regarded as being devoid of the markers expressed by differentiated blood cells, the lineage-specific antigens. However, recent work suggests that genes associated with the myeloid lineage are transcribed in mouse HSCs. Here, we explore whether myeloid genes are actually translated in human HSCs.

Expansion of human SCID-repopulating cells under hypoxic conditions.

It has been proposed that bone marrow (BM) hematopoietic stem and progenitor cells are distributed along an oxygen (O2) gradient, where stem cells reside in the most hypoxic areas and proliferating progenitors are found in O2-rich areas. However, the effects of hypoxia on human hematopoietic stem cells (HSCs) have not been characterized. Our objective was to evaluate the functional and molecular responses of human BM progenitors and stem cells to hypoxic conditions.

C1qRp defines a new human stem cell population with hematopoietic and hepatic potential.

The characterization of two distinct classes of hematopoietic stem cells based on CD34 expression and the ability of human bone marrow (BM) cells to differentiate into nonhematopoietic cells introduced new levels of complexity within the stem cell compartment. Here we report the identification and purification of a rare human stem cell population with hematopoietic and hepatic potential based on the expression of a receptor for the complement molecule C1q (C1qR(p)). We show that C1qR(p) is a positive marker of all BM-repopulating stem cells because it is expressed on both CD34(-) and CD34(+) stem cells from umbilical cord blood and adult BM.