Role of the endothelial adhesion molecule VCAM in murine cardiac allograft rejection.

Murine heterotopic cardiac isografts (C57B1/6----C57B1/6) undergo transient, non-destructive inflammation that is characterized by the acquisition of microvascular endothelial reactivity with the antibody MECA 32. Cardiac allografts (C57B1/6----DBA/2) undergo destructive inflammation that is characterized by the acquisition of reactivity with the antibody M/K-2, in addition to MECA 32. M/K-2 recognizes the murine endothelial adhesion molecule, VCAM-1. Hence, there appear to be antigen-dependent and antigen-independent forms of graft inflammation. Treatment of cardiac allograft recipients with 200 micrograms/day M/K-2 antibody retarded graft loss by only a few days, and did not interfere significantly with leukocytic infiltration, as detected by limiting dilution analysis of graft-reactive CTL, despite the fact that large amounts of M/K-2 could be detected on graft microvascular endothelia and in the peripheral blood as rejection progressed. These data indicate that VCAM is apparently not essential for the leukocytic infiltration and subsequent rejection of cardiac allografts, and is not involved in leukocytic infiltration of murine cardiac isografts.     

Experimental inflammation and tumor growth

Development and growth of primary (methylcholantrene or benzpyrene-induced) sarcomas in adjuvant arthritic rats were investigated and compared with the chemical carcinogenesis in normal healthy animals. When carcinogen and adjuvant were applied in the same time, tumor development and growth rate did not differ significantly from nonarthritic controls. When carcinogen was applied to rats with fully established arthritic disease, development and growth of tumors were significantly enhanced. In the latter case local and systemic adjuvant disease was more severe in tumor-bearing rats. Enhanced chemical carcinogenesis in arthritic rats can be explained by a defective immune responsiveness in the chronic stage of arthritis.     

Vascular endothelial differentiation in sponge matrix allografts

These studies test the hypothesis that vascular endothelia in sponge allografts may develop a function and phenotype resembling the high endothelial venules (HEV) in lymph nodes, thus facilitating the lymphocytic infiltration that is characteristic of allograft rejection. Using limiting dilution analysis to quantitate helper-T-cell accumulation at graft sites, immunohistologic analysis of graft reactivity with the HEV-specific monoclonal antibody MECA 325, and ex vivo lymphocyte-endothelial adhesion assays with graft tissues, we obtained evidence to suggest that HEV-like endothelia may develop at a graft site but that the process whereby lymphocytes accumulate at a graft site is more complex than was initially expected.     

Loss of tolerance to a maternal kidney transplant is selective for HLA class II: evidence from trans-vivo DTH and alloantibody analysis

We studied late graft rejection in a patient who had received a kidney transplant 9–10 years earlier from his mother and who had been off all immunosuppressive drugs for 7 years at the time of graft rejection onset. The mother differed for one HLA-A (A3) and one HLA-B (B62) antigen but had only a subtype mismatch at the HLA-DRβ1 locus (donor: DRβ1*1104; recipient: DRβ1*1102). A gradual rise in serum creatinine from 1.8 to 2.0 mg/dl at year 9 prompted a biopsy, which was negative for rejection (focal infiltrates but no tubulitis). Ten months later the patient’s creatinine had risen to > 3.4 mg/dl, and a second biopsy revealed extensive tubulitis, cellular rejection, and glomerular sclerosis. Sonicates of donor leukocytes triggered no delayed-type hypersensitivity (DTH) response above background (PBMC only) in the patient’s peripheral blood leukocytes obtained prior to year 9. A gradual recovery of antidonor DTH response between year 9 and 10 closely paralleled the change from tolerant to rejection status. Antidonor antibody was also undetectable in serum prior to year 9, but a donor-reactive antibody did develop at year 10.2 shortly after the peak of DTH response. The serum level of soluble donor HLA class I B62 antigen rose > 10-fold over prerejection level at the time of the biopsy-proven rejection, suggesting a possible trigger for both the cellular and humoral immune response. Nonetheless, we found no evidence for the de-velopment of humoral or cellular immunity to maternal HLA class I. Instead, DTH analysis of memory T cells of the patient obtained after rejection showed that a single maternal HLA DRβ1*1104 allopeptide, differing by two amino acids in sequence from the peptide of the recipient (DRβ1*1102), stimulated a strong memory DTH response. Similarly, we found an anti-HLA class II donor-specific antibody in serum that appeared to be crossreactive with DRβ1*1104 and DRβ1*1101 but not with the recipient DRβ1*1102 antigen. The data support the idea of a profound unresponsive state at both the cellular (DTH) and humoral level toward maternal HLA class I antigens that was not reversed even during late cellular rejection, despite the release of high levels of soluble HLA class I. Furthermore, the data suggest that DTH recovery was a close correlate of the onset of rejection and this “indirect” alloresponse, like the anti-donor alloantibody response that followed, was directed not to noninherited maternal HLA-A,B antigens but to the maternal HLA DRβ1*1104 subtype.     

Quantitation of antigen-specific immune responses in human immunodeficiency virus (HIV)-infected individuals by limiting dilution analysis

The lymphocyte proliferative response to recall antigens is lost following HIV infection. We sought to devise a means by which the functional immune status of persons in the early stages of HIV infection could be monitored quantitatively. The response to tetanus toxoid was examined in 45 HIV-infected individuals and 11 controls using conventional lymphocyte proliferative assays concurrently with limiting dilution analysis utilizing the secretion of interleukin-2 as the measure of a response. Our data show that the limiting dilution analysis detects tetanus toxoid-reactive T cells in 80% of those tested, as compared to only 44% by proliferation. However, the frequency of tetanus-reactive T cells in HIV-infected individuals (median frequency = 1/59,156) is decrease five-fold as compared to seronegative controls (median frequency = 1/11,599). Longitudinal studies demonstrated a time-dependent decrease in the frequency of tetanus-specific T cell responses in the HIV-infected individuals. Thus, the limiting dilution analysis is a quantitative approach for detecting antigen-specific T cells in HIV-infected individuals, and may be used to monitor changes in T cell function in HIV infection.     

Diffuse inflammatory pseudotumor of the testis,the epididymis and the spermatic cord

Inflammatory pseudotumors have been recognized in many parts of the body. A case of a diffuse variant which involved the testis, the epididymis and the spermatic cord is described. The patient had enlarged left testis for several months. Clinically, the lesion mimicred cancer. Histologically, the lesion contained hyalinized fibrous tissue with spindle cells, plasma cells and lymphocytes. Gradual involvement of vascular channels by the cellular elements of inflammatory pseudotumor was observed. Results of immunohistochemical studies showed a myofibroblast differentiation in the majority of spindle cells: intense antibody staining for smooth muscle actin, muscle specific actin, and vimentin. The ultrastructural findings, intracytoplasmic filaments with dense bodies, were also consistent with the myofibroblastic nature of these cells. The histiocyte differentiation of spindle cells is questionable in our case, because only scattered histiocyte-like cells showed positivity with the KP-1 (CD-3) antibody.     

Epidemiologic aspects of ischemic heart diseases in diabetic women]

The author discusses the relation of female gender, diabetes mellitus and cardiovascular disease relying upon the "WHO/Europe Health For All" statistical database, data of MEDLINE and the results of Framingham Heart Study. Cardiovascular disease is multifactorial in origin, and it is in connection with increasing prevalence and incidence of diabetes mellitus and hypertension. The mortality caused by ischaemic heart disease is 3-5 times higher if the patients suffer from diabetes mellitus as well. Diabetes mellitus alters the existing difference between males and females in the epidemiological characteristics of ischaemic heart disease. Pathomechanismus (such as metabolic disorders of lipids, hemostasis, endothelial function) are in connection with the changes of estrogen/progesteron balance, have a great role in this change. Diabetes mellitus still has been of significant epidemiological importance from the point of view of cardiovascular's incidence. The prevention of micro-, and macroangiopathy caused by diabetes mellitus beside the genetic factors is one of the most important parts of the epidemiological strategy.     

Trans vivo analysis of human delayed-type hypersensitivity reactivity.

There are clinical situations in which it may be advantageous to monitor delayed type hypersensitivity (DTH) responses, an index of cell-mediated immunity, without exposing patients directly to the challenge antigens. For example, transplant patients may be at risk for becoming sensitized to donor antigens if injected with donor antigen during traditional skin tests. We describe an alternative method for human DTH testing, which involves the transfer of human peripheral blood mononuclear cells plus antigen into the pinnae or footpads of naive mice. This induces a measurable DTH-like swelling response, which we refer to as the "trans vivo DTH response." As proof of principle, we provide data obtained during trans vivo DTH studies with tetanus toxoid, cytomegalovirus (CMV) and alloantigens. In general, human T cells must be co-localized with antigen and human macrophages to produce swelling responses, and such responses are antigen-specific and require prior antigen sensitization. Not only does this assay offer a simple, reliable clinical monitoring device, but it also provides a model with which to study the in vivo mechanisms of human DTH responses.