It is time for Chimerism
There are a number of reasons why this is an ideal time to launch the new journal Chimerism.
First, advances in molecular biological techniques over the past 10 years have resulted in tools to measure and characterize Mc that were previously unavailable. Also, it has only recently been appreciated that cells routinely traffic between the mother and fetus and that some cells persist decades later in respective individuals. Early studies suggest naturally acquired Mc has both detrimental and adverse consequences. A forum for interdisciplinary exchange is especially timely as investigators stand to profit by knowledge from colleagues in other research areas. For example, prior transplantation Mc studies generally tested female recipients of male grafts for male DNA, but were done prior to appreciation of persistent fetal Mc. Another example is shared insights may be garnered from pregnancy immunology (tolerance of the genetically disparate fetus) and transplantation (allograft) tolerance. Finally, another reason the time is ideal to launch Chimerism
is the need to establish standard techniques and measures of chimerism that are shared across disciplines as well as internationally.
Topics we will cover
Some cells traffic between a mother and fetus during pregnancy. Small numbers of cells, surprisingly, persist in respective hosts decades later. Chimerism refers to an individual harboring cells or DNA derived from another individual and microchimerism (Mc) in small amounts. The overall goal of Chimerism is to identify the wide breadth of consequences of naturally-acquired and iatrogenic chimerism across all of human health.1
In the first study of Mc in an autoimmune disease, elevated levels of fetal Mc were found in the blood of women with scleroderma compared to healthy women.2 Fetal Mc has since been investigated in primary biliary cirrhosis, thyroiditis, Sjogren's syndrome, polymorphic eruption of pregnancy and rheumatoid arthritis. Maternal Mc is found in her healthy adult progeny.3 Maternal Mc has been studied in neonatal lupus, systemic lupus and myositis. In neonatal lupus with heart block maternal cells in the heart were cardiac myocytes.4 Thus Mc could be immune targets, or alternatively could help repair tissues. Fetal Mc may be beneficial during pregnancy in women with rheumatoid arthritis as elevated levels significantly correlated with pregnancy-induced arthritis amelioration.5
Transplantation results in iatrogenic chimerism. Donor Mc has been proposed as facilitating graft acceptance. Until recently donor Mc was measured as male DNA in female recipients. It is now clear that women commonly have male DNA from prior pregnancies. In hematopoietic cell transplantation (HCT), graft-vs-host disease (GvHD) occurs more often if the donor is a woman with prior pregnancies. Female apheresis products were found to contain male Mc, potentially implicating fetal Mc in GvHD.6 In kidney, pancreas and islet transplantation serial serum samples were tested with a panel of specific quantitative PCR assays. Results indicated donor-specific Mc may become a useful non-invasive test for early rejection.7 Finally several groups are now therapeutically exploiting the principles of naturally-acquired Mc in their selection of donors for HCT.
In HCT donor cells provide an advantage against recurrent leukemia and other malignancies. By analogy, we asked whether fetal Mc contributes to protection from breast cancer, as it is known that women who have had children have a decreased breast cancer risk. Results support the hypothesis that fetal Mc is protective against breast cancer.8 On the other hand the converse question may be asked for selected other types of malignancies, i.e., whether microchimeric cells sometimes “go bad” and result in malignancy as suggested in some anecdotal reports.
The T lymphocyte is a key determinant of immune reactions between one's own cells and foreign cells. Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are characterized by critical deficiencies in CD4+T cells. Maternal Mc is currently being investigated in HIV and AIDS. Results will be examined for correlation with whether there is progression or non-progression to AIDS.
Diseases of the brain
The human brain represents an unexplored outpost for investigation of Mc. Recent studies of mice described maternal Mc in newborn brain and fetal Mc in maternal brain. Women who carried a trisomy 21 (Down syndrome) fetus are at increased risk of Alzheimer's disease raising the question whether accumulation of abnormal fetal cells is involved. Mc could have beneficial effects for example during normal development (maternal), countering of degenerative change (fetal) and in tumor immune surveillance (fetal or maternal). Conversely, adverse effects could include Mc as targets or effectors of immune damage or even neoplastic transformation. Some examples of major diseases to be investigated include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, primary intracranial tumors and HIV-associated dementia.
1. Adams KA, Nelson JL. Microchimerism: An investigative frontier in autoimmunity and transplantation. JAMA 2004; 291:1127-31.
2. Nelson JL, Furst DE, Maloney S, Gooley T, Evans PC, Bean MA, Ober C, Smith AJ, Bianchi DW. Microchimerism and HLA-compatible relationships of pregnancy in women with scleroderma. Lancet 1998; 351:559-62.
3. Maloney S, Smith AG, Furst DE, Myerson D, Rupert K, Evans PC, Nelson JL. Microchimerism of maternal origin persists into adult life. J Clin Invest 1999; 104:41-7.
4. Stevens AM, Hermes H, Rutledge R, Buyon J, Nelson JL. Maternal microchimerism has myocardial tissue-specific phenotype in neonatal lupus congenital heart block. Lancet 2003; 362:1617-23.
5. Yan Z, Ostensen M, Lambert NC, Guthrie KA, Nelson JL. Prospective study of cell-free fetal DNA and disease activity during pregnancy in women with inflammatory arthritis. Arthritis Rheum 2006; 54:2069-73.
6. Adams KM, Lambert NC, Heimfeld S, Tylee TS, Pang JM, Erickson TD, Nelson JL. Male DNA in peripheral blood stem cell apheresis products of female donors. Blood 2003; 15:3845-7.
7. Gadi, VK, Nelson JL, Boespflug N, Guthrie K, Kuhr C. Soluble donor DNA concentrations in recipient serum correlates with pancreas-kidney rejection. Clin Chem 2006; 52:379-82.
8. Gadi VK, Nelson JL. Fetal microchimerism in breast cancer. Can Res in press.